@article {pmid42320781,
year = {2026},
author = {Bashaw, AG and Roman-Ortiz, C and Gao, SX and Schier, LA and Borner, T and Kanoski, SE},
title = {Glucagon-like peptide-1 signaling in learning and memory: evidence, mechanisms, and therapeutic implications.},
journal = {Biological psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2026.06.006},
pmid = {42320781},
issn = {1873-2402},
abstract = {Glucagon-like peptide-1 (GLP-1) is primarily known for its role in glucose homeostasis and food intake control, and GLP-1 analogs (either as monotherapy or dual agonists) are commonly used for Type 2 Diabetes and obesity treatment in humans. Beyond these functions, the receptor for GLP-1 (GLP-1R) is widely expressed throughout the brain, including in the hippocampus and interconnected regions that contribute to learning and memory processes. Here we review emerging evidence supporting a role for GLP-1 signaling in promoting learning and memory function, particularly in dementia and other conditions that present hippocampal dysfunction. Evidence is synthesized from preclinical rodent models revealing that GLP-1 analog treatment improves deficits in memory function and hippocampal neuronal signaling processes in various models of dementia, aging, and metabolic disruption. While findings from human clinical trials and meta-analyses also show promise for GLP-1 analog-based treatment for memory disorders, results thus far are mixed, with many studies underpowered and/or lacking comprehensive memory evaluation. We describe several distinct yet non-mutually exclusive neurobiological mechanisms via which GLP-1R signaling can enhance memory, including blood-brain barrier penetration and direct action on hippocampal GLP-1Rs, improved peripheral and central insulin sensitivity, vagus nerve GLP-1R activation, and peripheral metabolic and inflammatory improvements. We conclude by emphasizing important considerations for future clinical trials for GLP-1 analogs in the treatment of Alzheimer's and other memory disorders, including focusing on metabolically vulnerable individuals, stratifying results by cardiovascular and metabolic status, and leveraging existing GLP-1 analogs and drug delivery approaches towards maximizing bioavailability and brain penetrance.},
}

@article {pmid42321014,
year = {2026},
author = {Kehmeier, MN and Famiano, A and Cullen, AE and Leonhardt, T and Ferguson, SJ and Snyder, M and McCurdy, CE and Tyrrell, DJ and Alkayed, NJ and Walker, AE},
title = {APOE4 negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP290852},
pmid = {42321014},
issn = {1469-7793},
support = {//John L. Luvaas Family Fund/ ; 23PRE1023169//AHA/ ; //Endocrine Technologies Core/ ; R01AG064106//HHS, National Institutes of Health/ ; P51OD011092//HHS, National Institutes of Health/ ; S10OD026701//HHS, National Institutes of Health/ ; },
abstract = {The APOEε4 allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between APOE genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous APOEε3 and APOEε4 mice (n = 19-20/group; ∼6 months old) that were fed a high-fat diet and were ovariectomized (OVX), OVX and supplemented with 17β-oestradiol, or left intact. In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilatation, which was rescued by 17β-oestradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-oestradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-oestradiol in the APOEε4 mice. In cerebral arteries and arterioles, 17β-oestradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro-inflammatory factors. Overall these results indicate that the APOE genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17β-oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX APOEε3 mice but not in APOEε4 mice. This suggests that 17β-oestradiol supplementation may have more cerebrovascular benefits for APOEε4 non-carriers. KEY POINTS: Females have twice the risk of Alzheimer's disease than males, and the APOEε4 genetic variant has a greater risk for Alzheimer's disease than the APOEε3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction between APOE genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied. We aimed to determine the impact of APOEε4 genotype on the cerebrovascular response to ovariectomy and oestradiol. We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function. This research suggests that APOE genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.},
}

@article {pmid42321855,
year = {2026},
author = {Gheibi, FS and Hosseini, L and Kalejahi, P and Dastgiri, S and Shafiee-Kandjani, AR and Noorazar, SG},
title = {Therapeutic potential of AdipoRon in cognitive, depressive, and anxiety disorders: a systematic review and meta-analysis.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01323-0},
pmid = {42321855},
issn = {1756-6606},
abstract = {Rising cases of cognitive disorders, depression, and anxiety underscore the need for new treatments, given the limited effectiveness and side effects of current options. AdipoRon targets adiponectin receptors and shows promise for protecting the brain, reducing inflammation, and supporting metabolism. This review examines preclinical data to determine whether AdipoRon consistently improves mood and cognitive function and to identify the underlying neurobiological pathways. We conducted a comprehensive literature search using PubMed, Embase, Web of Science, and Scopus, with no time limit, up to August 30, 2025. The quality of the selected studies was evaluated using the Collaborative Approach to Meta-Analysis and Review of Animal Studies (CAMARADES) checklists and the SYRCLE risk of bias tool. The studies found that AdipoRon treatment significantly reduced immobility in the forced swim test and had a significant anxiolytic effect in the open field test, especially in chronic unpredictable mild stress models. It also improved recognition memory in the novel object recognition test in models of Alzheimer's and Parkinson's diseases. Additionally, AdipoRon increased the expression of synaptic proteins, such as synaptophysin and PSD-95, in rodent models of these diseases. It also modulated the production of inflammatory cytokines. This review establishes AdipoRon's capacity to resolve depressive, anxious, and cognitive deficits in rodent models. Because the meta-analyses were based on a limited number of studies and substantial heterogeneity was observed across studies, the findings should be interpreted with caution. However, further well-designed preclinical and clinical investigations are essential to confirm these findings.},
}

@article {pmid42322185,
year = {2026},
author = {Lozupone, M and Dibello, V and Sardone, R and Zupo, R and Castellana, F and Bortone, I and Lampignano, L and Di Matteo, M and Moramarco, G and Dellegrazie, F and Daniele, A and Solfrizzi, V and Panza, F},
title = {Evaluating emerging amyloid-β centric drugs for the treatment of Alzheimer's disease.},
journal = {Expert opinion on emerging drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728214.2026.2693701},
pmid = {42322185},
issn = {1744-7623},
abstract = {INTRODUCTION: The amyloid cascade hypothesis provided a compelling rationale for Alzheimer's disease (AD) drug development, but many amyloid-β (Aβ)-targeted agents failed to show benefit. The present review article evaluated emerging Aβ-directed therapies, focusing on mechanisms, clinical efficacy, safety, and regulatory progress.

AREAS COVERED: The recent approvals of lecanemab and donanemab offered the first convincing evidence that reducing Aβ burden can modestly slow cognitive decline in early AD. Beyond these first-generation monoclonal antibodies, the pipeline includes next-generation antibodies with enhanced brain penetration (trontinemab), therapies designed also for presymptomatic intervention (remternetug tested for secondary prevention), and novel approaches targeting galectin-3 to disrupt Aβ aggregation and neuroinflammation. Active immunotherapies like UB-311 and small molecules such as ALZ-801, avoiding amyloid-related imaging abnormalities (ARIA), broaden the therapeutic horizon with potentially safer and more accessible options, but with no proven efficacy.

EXPERT OPINION: Clinical benefits for Aβ-centric therapies are modest, ARIA pose ongoing safety concerns, and high costs coupled with intensive monitoring limit accessibility. Regulators have begun to restrict approval to genetically defined subgroups according to apolipoprotein E genotype, underscoring the need for precision medicine. Therefore, while Aβ-centric therapies are incremental, they represent essential steps toward combination and precision strategies in the treatment of AD.},
}

@article {pmid42322653,
year = {2026},
author = {Cui, S and Jiang, Q and Chen, S},
title = {Locus coeruleus-norepinephrine system dysfunction: A new concept in cognitive aging and neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00910},
pmid = {42322653},
issn = {1673-5374},
abstract = {The role of the locus coeruleus in aging and neurodegenerative diseases has recently attracted attention. There is growing evidence of changes in the locus coeruleus-norepinephrine system in aging and neurodegenerative diseases, including increased tau accumulation, an inverted U-shaped pattern in the neuromelanin signal, and altered functional connectivity. This review summarizes the research applications and advancements in the study of cognitive aging and dysfunction of the locus coeruleus-norepinephrine system in neurodegenerative diseases. Recent evidence has suggested pathologic protein accumulation, locus coeruleus degeneration, reduced neuromelanin signal, and altered functional connectivity in neurodegenerative diseases in both human and animal models. Notably, the specific regions affected and the severity of these changes can vary subtly among different neurodegenerative disorders. Additionally, recent studies have shown a link between alterations in the locus coeruleus-norepinephrine system and both Alzheimer's and Parkinson's diseases. The possible mechanisms include promoting pathological protein accumulation, pro-inflammatory responses, synaptic plasticity dysfunction, oxidative stress, and blood- brain barrier dysfunction. Advanced experimental technologies have recently been applied to investigate the role of the locus coeruleus-norepinephrine system in aging, Alzheimer's disease, and Parkinson's disease. These advanced technologies, including optogenetic or chemogenetic methods and omics analysis help uncover the effects of specific locus coeruleus activation patterns and the locus coeruleus-related circuit mechanisms underlying its vulnerability during aging and neurodegenerative diseases. Thus, therapies targeting the locus coeruleus-norepinephrine system, including drugs and vagus nerve stimulation, have the potential for clinical application. Many studies have demonstrated the effects of adrenoreceptor-targeted drugs on cognitive function and Parkinson's disease, although some showed no effects. Limited data are available for norepinephrine-targeted drugs, which have demonstrated less-than-ideal results. Recent studies have demonstrated that vagus nerve stimulation can improve cognitive function in Alzheimer's disease and reduce the symptoms of Parkinson's disease, including gait function, suggesting that vagus nerve stimulation could be a new supplementary treatment for neurodegenerative diseases. Overall, the evidence reviewed suggests that the locus coeruleus-norepinephrine system is disrupted during aging and neurodegenerative diseases, and that this disruption can aggravate disease progression. Thus, the locus coeruleus-norepinephrine system is a potential therapeutic target in slowing disease progression. Future studies should focus on the locus coeruleus-norepinephrine system and use advanced experimental and neuroimaging technologies to reveal early pathological alterations and the underlying mechanisms of its vulnerability during aging and neurodegenerative diseases, along with exploring potential therapeutic approaches.},
}

@article {pmid42322910,
year = {2026},
author = {Liu, R and Wei, M and Xu, L and Qu, Z and Yu, JQ and Liu, Y and Zhang, WN and Zhang, D and Zhuang, C},
title = {A Keap1-Nrf2 protein-protein interaction inhibitor 4-95 ameliorates cognitive dysfunction by suppressing neuronal ferroptosis.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110134},
doi = {10.1016/j.bioorg.2026.110134},
pmid = {42322910},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder. With current therapies failing to halt clinical progression, identifying novel disease-modifying therapeutics is of paramount urgency. Although ferroptosis has emerged as a crucial driver of AD pathogenesis, effective pharmacological strategies targeting this pathway remain limited. Bioinformatic analysis revealed close associations among ferroptosis, oxidative stress, the Keap1-Nrf2 pathway, and AD. Compound 4-95, a selective Keap1-Nrf2 protein-protein interaction (PPI) inhibitor, significantly alleviated Erastin and RSL-3-induced ferroptosis in SH-SY5Y and HT-22 cells. In Aβ1-42-treated cell models, 4-95 dose-dependently decreased Aβ and p-Tau expression, while increasing the anti-ferroptotic proteins GPX4 and SLC7A11. Keap1 and GPX4 knockdown verified that 4-95 inhibits ferroptosis via the Keap1-Nrf2-GPX4 axis. In vivo, 4-95 markedly improved cognitive and spatial memory deficits in Aβ1-42-induced AD mice, promoted Nrf2 nuclear translocation, upregulated the downstream antioxidant targets HO-1 and NQO1, and attenuated neuronal injury. Collectively, the study reveals a new mechanism of a Keap1-Nrf2 PPI inhibitor that mitigates AD pathogenesis by directly inhibiting ferroptosis. This novel mechanism underscores a new class of disease-modifying candidates for AD treatment, representing a new therapeutic strategy for this devastating disorder.},
}

@article {pmid42323643,
year = {2026},
author = {Bouveret, Z and Pruvost, L and Trédan, O and Le Romancer, M and Poulard, C},
title = {How post-translational modifications impact glucocorticoid receptor function in human pathologies.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-03015-7},
pmid = {42323643},
issn = {1478-811X},
support = {ANR-22-CE13-0001-01//Agence Nationale de la Recherche/ ; },
abstract = {Glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family, which acts as a transcription factor when bound by glucocorticoid (GC) ligands. GR is expressed in nearly all tissue types and regulates essential processes such as inflammation, immune regulation and metabolism. Given its ubiquitous role, GR has frequently been associated with a wide range of illnesses, particularly in the fields of allergy, pulmonary, dermatology, rheumatology, or ophthalmology. It was reported that GCs either contribute to their development or serve as part of their treatment, making them the most prescribed drugs worldwide. GR activity and signaling is finely regulated by a network of post-translational modifications (PTMs). Indeed, PTMs can alter GR behavior and function by modifying its localization, stability, interaction with other proteins and transcriptional activity. Aside from the well-characterized phosphorylation events, additional PTMs are implicated in GR activity and their dysregulation has been described in various diseases. This review provides an integrated overview of current knowledge on GR PTMs, highlighting both mechanistic insights and their relevance in disease. We will present how aberrant PTMs contribute to extremely prevalent diseases, such as cancer, chronic inflammatory diseases, Alzheimer's disease and other neurological diseases. Special attention will be given to the specific readers of these PTMs and to the enzymes catalyzing these modifications, as they represent promising therapeutic targets.},
}

@article {pmid42323655,
year = {2026},
author = {Monteverdi, A and Cotta Ramusino, M and Conca, F and Augello, A and Totaro, C and Grasso, PA and Castelnovo, A and Lorenzi, RM and Terzaghi, M and Farina, LM and Costa, A and Pichiecchio, A and Cappa, SF and Gandini Wheeler-Kingshott, C and Palesi, F and D'Angelo, E},
title = {Virtual brain and electroencephalography explain the variance of memory alterations in mild cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02114-4},
pmid = {42323655},
issn = {1758-9193},
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive.

METHODS: Here Aβ/tau biomarkers were used to distinguish positive (MCI[+]- prodromal Alzheimer's disease) and negative (MCI[-]) subjects in a cohort of 30 MCI patients (18 MCI[+] and 12 MCI[-]). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance.

RESULTS: While virtual brain simulations did not reveal E/I differences between MCI[+] and MCI[-], a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI[+] largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert.

CONCLUSIONS: This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.},
}

@article {pmid42324743,
year = {2026},
author = {Sakagami, S and Yoshida, Y and Uemura, S and Kumamoto, T and Tsukamoto, R and Nishi, T and Kawano, S and Fukuoka, K and Ino, H and Hamamura, K and Ohdo, S and Matsunaga, N},
title = {Benzbromarone as a Novel Candidate for Preventing Alzheimer's Disease: Evidence From Real-World Data Screening and in Vitro Validation.},
journal = {Clinical and translational science},
volume = {19},
number = {7},
pages = {e70650},
doi = {10.1111/cts.70650},
pmid = {42324743},
issn = {1752-8062},
mesh = {Humans ; *Benzbromarone/therapeutic use/pharmacology ; *Alzheimer Disease/prevention & control/epidemiology ; *Drug Repositioning ; Female ; Male ; Japan/epidemiology ; *Uricosuric Agents/pharmacology/therapeutic use ; Aged ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Incidence ; Cell Line, Tumor ; },
abstract = {Drug development for Alzheimer's disease (AD) remains challenging, with only a 0.4% success rate from Phase I trials to regulatory approval. Drug repositioning leverages existing approved drugs to identify promising drug alternatives, particularly when combined with real-world data (RWD) and target trial emulation. In this study, we comprehensively screened 1,241 approved drugs using a large-scale Japanese claims database (n = 2,090,465; 2005-2023). We identified patients newly prescribed a study drug and applied an active-comparator, new-user design. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the covariates. The primary outcome was incident AD, defined using ICD-10 codes (F00 and G30). We estimated cumulative incidence using IPTW-adjusted Kaplan-Meier analysis and Cox proportional hazards models and conducted sensitivity analyses using Fine-Gray competing risk models, empirical calibration with negative control outcomes, and E-value estimation. We performed in vitro validation using Aβ-Tet-ON SH-SY5Y cells and quantified Aβ expression using western blotting. Benzbromarone, a uricosuric agent, was associated with a decreased risk of AD onset (adjusted HR: 0.54, 95% CI: 0.41-0.71, p < 0.05 post-FDR correction); this association remained robust across sensitivity analyses. In vitro, benzbromarone reduced Aβ protein expression in SH-SY5Y cells in a dose-dependent manner, even following transcriptional blockade, suggesting a posttranscriptional regulatory mechanism. In conclusion, using a combined approach of RWD-based pharmacoepidemiology and in vitro validation, we identified benzbromarone as a novel candidate potentially associated with reduced AD risk. Our findings highlight the potential of drug repositioning strategies to accelerate AD drug discovery, promoting further mechanistic and clinical investigations.},
}

Humans
*Benzbromarone/therapeutic use/pharmacology
*Alzheimer Disease/prevention & control/epidemiology
*Drug Repositioning
Female
Male
Japan/epidemiology
*Uricosuric Agents/pharmacology/therapeutic use
Aged
Amyloid beta-Peptides/metabolism
Aged, 80 and over
Incidence
Cell Line, Tumor

@article {pmid42324842,
year = {2026},
author = {Ugale, V and Sharon, N and Salunkhe, C and Salunkhe, J and Lokwani, D and Patil, K and Reddy, PN and Kulkarni, P},
title = {Naphthalene-4H-Chromene Molecular Hybrids as Dual Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70338},
doi = {10.1002/ddr.70338},
pmid = {42324842},
issn = {1098-2299},
support = {RGSTC/File-2024/DPP-309/CR-20/332//Rajiv Gandhi Science and Technology Commission/ ; TAR/2021/000140//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; CRG/2022/004365//Department of Science and Technology (DST)-Science and Engineering Research Board (SERB)/ ; KBCNMU/RGSTC/Sanction Order/199//Kavayitri Bahinabai Chaudhari North Maharashtra University (KBCNMU)/ ; },
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis ; Animals ; *Alzheimer Disease/drug therapy ; Mice ; *Naphthalenes/chemistry/pharmacology ; *Benzopyrans/chemistry/pharmacology ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Molecular Docking Simulation ; Male ; Humans ; Scopolamine ; Cell Line ; Structure-Activity Relationship ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)-4H-chromene derivatives 4(a-n) by a one-pot three-component reaction with adequate synthetic yield and purity. Naphthalene-chromene hybrids were synthesized by formation of two C─C bonds and one C─O bond in a single synthetic step. All synthesized compounds were tested for safety and efficacy using in vitro and in vivo studies. Compounds were found devoid of cytotoxicity in BV-2 cells. Most of the synthesized compounds have shown moderate to good inhibitory activity against cholinesterase enzymes. These compounds were found to be more selective towards acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE). Compound 4 m has shown highest inhibitory potency against AChE (AChE, IC50 = 1.08 µM; BuChE, IC50 = 82.59 µM). The prototype compound (4 m) from in-vitro screening was found to be safe in acute oral toxicity followed by histopathological analysis. Compound 4 m was evaluated for in vivo efficacy in scopolamine-induced cognitive impairment model in mice. It significantly reversed the cognitive deficit in neurobehavioral tests. Pre-treatment with 4 m have balanced key biochemical markers involved in the oxidative stress and cognitive functions. The compound 4 m alleviated neuronal tissue damage caused by scopolamine as indicated in the histological study. Molecular docking analysis also reconfirmed the binding affinity of 4 m at cholinesterase enzymes. Taken together, these findings supported the emergence of 4 m as a potential cholinesterase inhibitor for the treatment of AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/chemical synthesis
Animals
*Alzheimer Disease/drug therapy
Mice
*Naphthalenes/chemistry/pharmacology
*Benzopyrans/chemistry/pharmacology
Acetylcholinesterase/metabolism
Butyrylcholinesterase/metabolism
Molecular Docking Simulation
Male
Humans
Scopolamine
Cell Line
Structure-Activity Relationship

@article {pmid42325226,
year = {2026},
author = {Alhowail, AH and Al Mouslem, AK and Almatrafi, MA and Aldubayan, MA},
title = {Semaglutide in cognitive dysfunction: neuroprotective potential, clinical trial limitations, and a prevention-focused framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1851072},
pmid = {42325226},
issn = {1663-4365},
abstract = {Metabolic dysfunction is increasingly recognized as a pivotal factor in cognitive decline and neurodegenerative diseases, such as Alzheimer's disease (AD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs), notably the long-acting agonist semaglutide, exhibit significant metabolic efficacy and pronounced neuroprotective effects across a broad spectrum of preclinical models. This is corroborated by extensive epidemiological studies that consistently link GLP-1RA use with a decreased incidence of dementia. Nevertheless, promising preclinical and observational findings have not been mirrored in clinical success for the treatment of established AD. Recent negative outcomes from the pivotal phase 3 EVOKE and EVOKE+ trials, which demonstrated no clinical benefit of oral semaglutide in patients with early AD, have resulted in a notable translational paradox. This review critically examines the mechanistic, preclinical, epidemiological, and clinical evidence concerning the impact of semaglutide on cognitive function to reconcile these conflicting findings. Preclinical studies have revealed complex neuroprotective mechanisms, including suppression of neuroinflammation, restoration of metabolic function, and activation of pro-survival pathways. Conversely, clinical trials in symptomatic AD have been unsuccessful, although modest and clinically insignificant changes in cerebrospinal fluid biomarker levels have been observed. We propose the hypothesis that the current body of evidence is consistent with a prevention-focused model, wherein semaglutide's primary value may lie in modifying the upstream metabolic and inflammatory drivers of neurodegeneration, such as those prevalent in vascular and metabolic cognitive impairment, rather than reversing established amyloid-driven AD pathology. This hypothesis, however, remains speculative and requires prospective validation in appropriately designed trials. This review seeks to resolve the apparent contradictions in the literature and propose future research directions centered on appropriate patient populations and therapeutic windows.},
}

@article {pmid42325271,
year = {2026},
author = {Liang, C and Jiang, W and Chen, J and Turner, JA and Calhoun, VD and Abbott, CC and Jiang, R and Fu, Z and Wu, L and Wang, X and Qi, S and Yuan, Y},
title = {Longitudinally altered default mode network and insula multimodal brain pattern in end-stage renal disease during sustained hemodialysis treatment.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116008},
pmid = {42325271},
issn = {2589-0042},
abstract = {Hemodialysis (HD) is the predominant treatment for end-stage renal disease (ESRD). Despite the efficacy of HD, the neurobiological underpinnings underlying high-risk complications remain unclear. In this study, using unsupervised fusion of functional and structural MRI, we identified a longitudinally altered default mode network (DMN)-insula pattern in ESRD receiving HD over 1-year follow-up (n = 39). This pattern was associated with cognition, and its related genes were enriched in biological processes involving DNA damage and repair, energy metabolism, and cellular activation. The baseline DMN-insula pattern demonstrated potential predictive value for follow-up cognition in ESRD. More importantly, these brain-cognition associations were validated in independent high-risk complications cohorts, including major depressive disorder (n = 60), mild cognitive impairment (n = 291), and Alzheimer's disease (n = 77) by extracting the corresponding brain features and assessing their correlations with cognition. Collectively, this study may help researchers better understand the underlying mechanisms of ESRD receiving HD from a multimodal neuroimaging and molecular perspective.},
}

@article {pmid42325273,
year = {2026},
author = {Hao, W and Yu, X and Zhou, Q and Jia, Y and Su, X and Yu, Y and Wang, Y and Wang, J and Liu, C},
title = {Different modulation patterns of theta and gamma dual-site HD-tACS on cognitive impairment.},
journal = {iScience},
volume = {29},
number = {6},
pages = {116138},
pmid = {42325273},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is characterized by impaired local network integration and long-range connections. Theta and gamma oscillations are critical for cognitive function, so this study used dual-site fronto-temporoparietal junction (TPJ) high-density transcranial alternating current stimulation (HD-tACS) to explore its frequency-specific effects on brain networks and cognition. Thirty-six AD patients were randomized 1:1:1 to 6Hz-tACS, 40Hz-tACS and sham stimulation targeting bilateral fronto-TPJ cortex for four weeks. Cognitive functions were assessed at baseline, post-treatment and 8-week follow-up. TMS-EEG and voxel-based distance-related functional connectivity analysis evaluated network changes. Both active stimulation groups showed sustained cognitive improvements for eight weeks compared to the sham stimulation group (all p < 0.017). 40Hz-tACS also enhanced language function (p < 0.025). 6Hz-tACS increased anterior functional connections and anterior-to-posterior information flow, while 40Hz-tACS increased posterior connections and posterior-to-anterior flow, closely linked to cognitive improvements. These effects are oscillation frequency-dependent, supporting cognitive improvement in AD.},
}

@article {pmid42325435,
year = {2026},
author = {Liu, C and Zhu, Z and Lin, H and Bush, WS and Jenq, RR and Cominelli, F and Pillai, JA and Haines, JL and Zhu, X and Xu, R and Williams, SM and Cheng, F and Zhang, L},
title = {The gut-brain axis in Alzheimer's disease: early detection, microbial metabolites, mechanisms, and therapeutic opportunities.},
journal = {Frontiers in molecular biosciences},
volume = {13},
number = {},
pages = {1735332},
pmid = {42325435},
issn = {2296-889X},
abstract = {Alzheimer's disease (AD), the leading cause of dementia worldwide, imposes a growing clinical and societal burden, yet no therapies have been proven to alter its progression despite decades of intensive research. As traditional targets have yielded limited success, attention has shifted to modifiable upstream pathways, notably the gut-brain axis, a bidirectional system linking gut microbiota with CNS function. Emerging evidence indicates that microbial dysbiosis may influence key processes leading to AD, including neuroinflammation, amyloid and tau pathology, and cognitive decline. While microbiome composition is associated with AD, it remains unclear at which stage-preclinical, mild cognitive impairment (MCI), or AD dementia-these differences first arise, or how specific risk bacteria and metabolites contribute to progression. The precise roles of these microbes and metabolites in AD pathology or brain resilience also remain poorly understood, and few microbiome-targeted treatments have been validated in humans. Existing reviews often overlook host-specific factors that influence microbiome composition and confound associations with AD. To bridge these gaps, we summarize human studies published in the past 5 years. The literature suggests that gut microbial changes may precede clinical symptoms, with consistent dysbiosis observed in AD patients. We adopt a microbiome-centered perspective emphasizing bacteria-driven and metabolite-driven mechanisms, each playing distinct yet complementary roles in neural and bloodstream pathways. These pathways offer potential targets for microbiome-based prevention and treatment but require more human validation. Future studies should leverage longitudinal, multi-omics approaches and artificial intelligence (AI) tools while rigorously accounting for confounders to improve early detection and develop personalized therapies for AD.},
}

@article {pmid42325550,
year = {2026},
author = {Li, X and Chen, H and Xu, P and Guo, X and Gao, J and Yao, D and Wang, Y and Wang, T and Liu, B and Yuan, J},
title = {Exosomes: A new frontier in the treatment of neurological diseases.},
journal = {iScience},
volume = {29},
number = {7},
pages = {116331},
pmid = {42325550},
issn = {2589-0042},
abstract = {Exosomes (Exos) are an essential class of extracellular vesicles enriched with a wide range of biologically active molecules, which gives them a unique advantage in participating in intercellular signaling and communication and serving as carriers for drug delivery. Exo-based diagnostic and therapeutic strategies are currently hot topics in disease research. Owing to their naturally low immunogenicity, good biocompatibility, ability to penetrate the blood‒brain barrier (BBB), and engineered modifications, exos have significant advantages and possible applications in the treatment of nervous system diseases. Due to the serious harm of neurological diseases to human health, they have been widely studied by researchers. Exos can be administered in a variety of ways, including intranasal administration, intracranial administration, local stereotactic injection, and encapsulation in biomaterials, each of which has its own advantages and disadvantages. However, several requirements need to be met before exo-based therapies can be implemented, such as the standardization of isolation and purification techniques, an in-depth understanding of the mechanism of action, and safety assessments and regulation for clinical translation. The aim of this review is to provide a comprehensive overview of the biogenesis, molecular composition, function, and delivery modes of exos and their therapeutic roles and mechanisms in neurological diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and stroke) and to discuss the current challenges and future perspectives to support ongoing research and clinical applications.},
}

@article {pmid42327033,
year = {2026},
author = {Mostowfi, N and Foreman, R and Wang, J and Khoury, R and Albanese, A and Ma, QL and Cohn, W and Petzinger, G and Jakowec, M and Ahmed, SK and Seidler, PM},
title = {Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.09.731185},
pmid = {42327033},
issn = {2692-8205},
abstract = {Pathological tau aggregates drive neuronal dysfunction in Alzheimer's disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the development of a coumarin-based small-molecule series that disaggregates tau fibrils and oligomers through a stacking-driven co-assembly mechanism. Structure-activity relationships identified PT-13 as a lead compound that inhibits tau seeding by AD brain-derived matter and reduces aggregate burden measured across both fibrillar and oligomeric tau species. Mechanistic studies demonstrate that disaggregation does not generate soluble oligomeric intermediates, addressing a central question in the field. PT-13 is brain-penetrant and well tolerated in vivo. In a tauopathy mouse model, PT-13 treatment reduces tau pathology while preserving behavioral function, proteasome capacity, and synaptic integrity. These findings establish small-molecule tau disaggregation as a viable therapeutic strategy and provide a molecular framework for the design of aggregate-directed therapeutics in neurodegeneration.},
}

@article {pmid42318437,
year = {2026},
author = {Dinnerstein, E},
title = {"Doctor, if it were you, which would you choose?": Navigating personal preference questions in anti-amyloid immunotherapy selection.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70373},
pmid = {42318437},
issn = {2352-8729},
abstract = {The approval of lecanemab and donanemab represents a watershed moment in Alzheimer Disease (AD) treatment, yet clinicians face a novel challenge: guiding patients through treatment selection when head-to-head comparative data are absent. When confronted with the question "What would you do if you were me?", clinical providers must balance evidence-based medicine with the therapeutic alliance. This perspective examines the ethical, practical, and relational dimensions of responding to personal preference queries in the context of anti-amyloid immunotherapy selection, offering a framework for authentic engagement that honors both professional boundaries and patient-centered care.},
}

@article {pmid42318555,
year = {2026},
author = {Yadollahi Khales, A and Ghaedi, K and Esmaeili, F and Noorbakhshnia, M and Etemadifar, M},
title = {Plasma lncRNA signature of upregulated ATP2B1-AS1 and downregulated RPL21P28 correlates with diagnosis and cognitive severity in Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1739935},
pmid = {42318555},
issn = {1663-4365},
abstract = {BACKGROUND: The non-invasive biomarkers have considerable effects in determination and treatment of Alzheimer's disease (AD). The specificity and stability of the circulating long non-coding RNAs (lncRNAs) have made them suitable options in disease management. The aim of this study was discovering and clinically confirming a new plasma lncRNA signature and the underlying regulatory mechanisms.

METHODS: In a two-stage research, the preliminary bioinformatic screen of public transcriptomic data (GEO: GSE63060) found candidate lncRNAs. Then the level of the major candidates, ATP2B1-AS1 and RPL21P28, were validated by Real-Time qPCR in plasma of 25 AD patients and 25 healthy controls. The diagnostic performance was appraised by the Receiver Operating Characteristic (ROC) curve analysis and the presumed functions were described by a competing endogenous RNA (ceRNA) network.

RESULTS: Our study established concurrent ATP2B1-AS1 upregulation and RPL21P28 downregulation in Alzheimer's patient plasma (p < 0.001). This highly discriminatory two-lncRNA signature produced an area under the curve (AUC) of 0.81 for ATP2B1-AS1 and 0.83 for RPL21P28. Based on MMSE scores, the expressions of both lncRNAs were significantly correlated with the level of cognitive impairment. These lncRNAs were also showed a correlation to important regulation mechanisms by our ceRNA network analysis, with RPL2B1P28 linked to synaptic functional genes and ATP2B1-AS1 to neurodevelopment.

CONCLUSION: ATP2B1-AS1 and RPL21P28 plasma levels present specific AD biomarker signature. These lncRNAs show great potentials in designing a non-invasive blood test that can be used for early diagnosis and disease follow-up. It also establishes new areas for intervention therapy research.},
}

@article {pmid42319641,
year = {2026},
author = {Jetsonen, V and Välimäki, T and Selander, T and Kuvaja-Köllner, V and Martikainen, J and Koivisto, AM},
title = {Different family caregiver- and care recipient-related factors are associated with the cost of care in the early, mild, and moderate stages of Alzheimer's disease in Finland: A 5-year ALSOVA study.},
journal = {The European journal of health economics : HEPAC : health economics in prevention and care},
volume = {},
number = {},
pages = {},
pmid = {42319641},
issn = {1618-7601},
abstract = {PURPOSE: Alzheimer's disease (AD) accounts for a significant proportion of health and social care costs. We studied family caregiver (FC), care recipient (CR), and formal care provider-related factors, which are associated with the cost of care in different stages of AD in Finland.

METHODS: A 5-year follow-up was conducted with 231 individuals with AD (CRs) and their FCs as a part of the ALSOVA project. The data was collected between 2002 and 06. Significant factors associated with costs were identified using a stepwise backward elimination procedure. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory (NPI).

RESULTS: Across all stages of AD, each additional year of CR's education was associated with a 3.4% reduction in costs (rate ratio [RR] 0.966, 95% CI 0.940-0.993). Conversely, a one-point increase on the Neuropsychiatric Inventory was associated with a 1.8% increase in costs (RR 1.018, 95% CI 1.011-1.025). CR's neuropsychiatric symptoms (RR 1.028, 95% CI 1.010-1.047) and male FC (RR 1.756, 95% CI 1.266-2.437) were associated with increased total costs in early AD, CR's comorbidities (RR 1.138, 95% CI 1.068-1.212) and FC's burden (RR 1.032, 95% CI 1.012-1.053) in mild AD and FC being a spouse (RR 1.451, 95% CI 1.105-1.905) in moderate AD. No formal care provider-related factors were associated with total costs in any stage of AD.

CONCLUSIONS: This study reveals several factors that may be manageable to control the costs of AD. Comprehensive prevention, evaluation, and treatment of a CR's neuropsychiatric symptoms and comorbidities should be executed early. Informal care can act as a substitute for formal care in early-stage AD, and supportive measures toward FCs should be considered.},
}

@article {pmid42320774,
year = {2026},
author = {Ren, L and Liu, S and Sun, X and Zhang, Y and Wang, P and Liu, L and Chen, LL},
title = {Ditan Decoction alleviates glutamate excitotoxicity in an Aβ-induced Alzheimer's disease-like model through the regulation of ERBB2/PI3K/AKT signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122084},
doi = {10.1016/j.jep.2026.122084},
pmid = {42320774},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD), as the most prevalent form of dementia among the elders, poses a major global health challenge. Ditan Decoction (DTD), a classic prescription from traditional Chinese medicine, demonstrates potent capacity against neurological disorders. Nevertheless, the specific components of DTD and its mechanisms in treating AD remain unclear.

AIM OF THE STUDY: The study was designed to investigate the underlying substance basis and molecular mechanisms of DTD in treating Aβ1-42-induced cognitive decline in rats.

MATERIALS AND METHODS: The AD model rats established by Aβ1-42 injection were subjected to cognitive function assessment through Y-maze, Morris water maze and novel object recognition tests. Neuronal damage and dendritic spine integrity were evaluated by Nissl and Golgi staining. The constituent assignment of DTD in vitro and in vivo were accomplished by LC-MS, and potential targets for AD treatment were predicted through network pharmacology, broad-target metabolomics, molecular docking and molecular dynamics simulations. Immunofluorescence and neurotransmitter assay served to analyze neuronal activation levels and glutamate content. Protein expressions of signal pathway were detected in hippocampus and validated by serum pharmacology in HT22 cells using Western blot analysis.

RESULTS: DTD treatment significantly alleviated the cognitive dysfunction in AD model rats. LC-MS analysis identified 268 compounds in DTD, with 23 active ingredients absorbed in vivo. Integrated analyses combining network pharmacology, metabolomic profiling, molecular docking, and molecular dynamics simulations indicated that DTD may exert therapeutic effects against AD by lowering glutamate levels in hippocampus via the regulation of ERBB2/PI3K/AKT signaling pathways. DTD upregulated the expression of ERBB2 and p-AKT, reduced glutamate-induced neuronal activation levels and hippocampal glutamate content, and elevated the level of synaptic proteins PSD95, Syn1 and NR2A/B, thereby improving the structural and functional integrity of synapses. Cell tests confirmed that DTD alleviated glutamate-induced excitotoxicity and synaptic dysfunction in HT22 cells via ERBB2/PI3K/AKT pathway, which was abolished by ERBB2 inhibitor AG-825 and PI3K inhibitor LY294002.

CONCLUSIONS: This study elucidates the neuroprotective mechanism of DTD within AD model rats. DTD improves synaptic dysfunction by reducing hippocampal glutamate concentrations and counteracting glutamate-mediated excitotoxicity via the ERBB2/PI3K/AKT signaling pathway.},
}

@article {pmid42318047,
year = {2026},
author = {Wei, YT and Li, L and Xie, WT and Wang, Y and Zhao, YR and Zhang, RZ and Ma, L and Yan, XK},
title = {Altered Effective Connectivity Within the Frontoparietal Network in Alzheimer's Disease and Its Modulation by Acupuncture: A Resting-State fMRI Study.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {601136},
pmid = {42318047},
issn = {1176-6328},
abstract = {PURPOSE: Alzheimer's disease (AD) is increasingly prevalent, yet how acupuncture modulates cognitive brain networks remains unclear. We used resting-state fMRI (rs-fMRI) to examine whether acupuncture prescription regulates effective connectivity within the frontoparietal network (FPN) in AD.

PATIENTS AND METHODS: Sixty AD patients were randomized to donepezil alone (drug group) or acupuncture plus donepezil (acupuncture group) for 6 weeks (n=30/group). Seven healthy controls were scanned once. Global cognition was assessed with MoCA-B. Independent component analysis identified the FPN, and Granger causality analysis quantified directed effective connectivity before and after treatment.

RESULTS: Both interventions improved MoCA-B (P<0.05), with larger gains in the acupuncture group (P<0.05). Relative to controls, AD showed FPN disruption with compensatory reorganization. Decreased connectivity was observed from the left middle temporal gyrus (MTG) to the right inferior parietal lobule (IPL), and from the left median cingulate/paracingulate gyri (P<0.05). Increased connectivity emerged from the right IPL and left cingulate/paracingulate to the left MTG, and from the right IPL to the left medial frontal gyrus (orbital part) (P<0.05). The right IPL and left MTG were core FPN nodes. Post-treatment, the drug group showed reduced right IPL→left orbital medial frontal connectivity, whereas the acupuncture group showed reduced right IPL→left MTG connectivity (P<0.05). Between-group comparisons indicated acupuncture-specific modulation of right insula→left MTG and left precuneus→left MTG connectivity (P<0.05).

CONCLUSION: Acupuncture combined with donepezil provides superior cognitive benefits and selectively reshapes directed FPN interactions, supporting a network-level mechanism involving frontal-parietal-temporal integration.},
}

@article {pmid42311735,
year = {2026},
author = {Harikumar, N and Gupta, M and Al Janabi, T and Mand, KK},
title = {A Severe Symptomatic Case of Amyloid-Related Imaging Abnormalities After Donanemab Infusion.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e109045},
pmid = {42311735},
issn = {2168-8184},
abstract = {Amyloid-related imaging abnormalities (ARIA) are known complications of anti-amyloid monoclonal antibody therapy for Alzheimer's disease. Although many cases are asymptomatic, severe presentations can mimic stroke or toxic encephalopathy. This case highlights a rare presentation of ARIA with myoclonic movements and acute encephalopathy following donanemab infusion. We report a 75-year-old woman with Alzheimer's disease who developed acute confusion, hallucinations, and involuntary movements one day after her sixth donanemab infusion. Stroke workup was negative. MRI demonstrated findings consistent with both ARIA-E and ARIA-H. She was treated with high-dose intravenous methylprednisolone, followed by an oral prednisone taper, which resulted in gradual neurological improvement. Clinicians must maintain a high suspicion for ARIA in patients receiving anti-amyloid therapy who present with acute neurologic decline. Early MRI evaluation and prompt corticosteroid treatment may improve outcomes.},
}

@article {pmid42312520,
year = {2026},
author = {R, N and Dubey, S and Kumar, D and Walhekar, V and Tiwari, P},
title = {In Silico Prediction, Characterization, and Pre-clinical Appraisal of the Neuroprotective Effect of the Methanolic Extract of Cassytha filiformis.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026456568260601100209},
pmid = {42312520},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a severe neurodegenerative disorder that progressively worsens with age. Medicinal plants have demonstrated potential for the management of AD. Cassytha filiformis, a native plant of the Indian subcontinent, has been reported to exhibit antioxidant activity, which could be beneficial in neurodegenerative disorders.

METHODS: This study evaluates the anti-neurodegenerative effect and possible mechanism of action of a methanolic extract of Cassytha filiformis (MECF). Two compounds, AC-2 and AC-4, were isolated from the extract and assessed for cognitive behavior using the Morris water maze and probe test, followed by evaluation of antioxidant, neurochemical, and anti-inflammatory parameters, as well as in silico studies.

RESULTS: Neurochemical abnormalities (acetylcholinesterase (AChE), NMDA (N-methyl-Daspartate), dopamine (DA)), neuro-inflammatory markers (TNF-α, IL-6), and antioxidant parameters (superoxide dismutase (SOD), lipid peroxidation (LPO), nitric oxide (NO)) were evaluated. Histological examination of brain cells assessed the regenerative impact of the isolated compounds. Antioxidant levels and neuroinflammation were significantly reduced (p < 0.05) in the MECF-, AC-2-, and AC-4-treated groups. Additionally, superoxide dismutase and catalase levels were significantly increased in the treated groups. Acetylcholine, NMDA, and dopamine levels showed marked improvement. Histopathological analysis revealed neuroregeneration in the test groups, and hematological evaluations supported these findings by demonstrating normalization of elevated blood profiles observed in the scopolamine-induced groups.

DISCUSSION: MECF and its isolated compounds, AC-2 and AC-4, exhibited notable antioxidant and neuro-anti-inflammatory properties, enhancing cognitive function, learning, and memory. The observed neuroprotective effects suggest a potential therapeutic role for these compounds in the management of AD.

CONCLUSION: Phenolic compounds present in AC-2 and AC-4 may be integral to the mechanism of action of MECF. Further investigations, including clinical validation, are necessary to explore the therapeutic potential of MECF, AC-2, and AC-4 in AD treatment.},
}

@article {pmid42313307,
year = {2026},
author = {Saini, K and Dhiman, P},
title = {Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42313307},
issn = {1573-4978},
mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/therapy/pathology/immunology ; Animals ; Signal Transduction ; *Neuroinflammatory Diseases/metabolism/pathology/immunology ; Blood-Brain Barrier/metabolism ; Cytokines/metabolism ; Astrocytes/metabolism ; },
abstract = {Neuroinflammation has been identified as a major component to the pathogenesis and progression of many neurodegenerative illnesses, going beyond its traditional role as a protective immune response within central nervous system (CNS). There is growing evidence that persistent activation of peripheral immune pathways, microglia and astrocytes causes progressive neurodegeneration, synaptic loss and progressive neurodegeneration. This review examines the mechanisms of microglia- driven neuroinflammatory signaling and its involvement in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Key neuroinflammatory mechanisms covered in depth including microglial activation, astrocyte reactivity, peripheral immune cell infiltration, cytokine dysregulation, and blood brain barrier (BBB) disruption. This review also emphasizes the role of neuroinflammation in acute neurological symptoms and mental and cognitive impairments. Glial activation markers, inflammatory cytokines, BBB proteins and kynurenine pathway metabolites are emerging as promising biomarkers for disease diagnosis and monitoring. Additionally, the potential of new mathematical and systems level computational models to describe intricate neuroimmune interactions and forecast the course of disease and treatment results is investigated. Current and emerging therapies targeting neuroinflammation include anti-inflammatory and immunomodulatory drugs, lifestyle interventions, stem cell approaches, gene-editing technologies and nanoparticle-based drug delivery systems. Despite significant progress, translating preclinical findings into effective clinical therapies remains challenging. Future developments in integrative neuroimmune modeling, biomarker-guided therapies and precision medicine may make it possible to create individualized treatments plans targeted at reducing neuroinflammation and enhancing the course of neurodegenerative illnesses.},
}

Humans
*Microglia/metabolism/pathology/immunology
*Neurodegenerative Diseases/metabolism/therapy/pathology/immunology
Animals
Signal Transduction
*Neuroinflammatory Diseases/metabolism/pathology/immunology
Blood-Brain Barrier/metabolism
Cytokines/metabolism
Astrocytes/metabolism

@article {pmid42314102,
year = {2026},
author = {Ganesh, A and Smith, EE and Mostert, J and Strijbis, EM and Schoonheim, MM and Xia, C and Nadeau, Y and Leavitt, VM and Kalia, LV and Engelborghs, S and D'Haeseleer, M and McPherson, T and Cutter, GR and Koch, MW and , },
title = {Phase 2 Futility Trials in Alzheimer Disease and Mild Cognitive Impairment: A Cohort Analysis of the ADNI Data Set.},
journal = {Neurology},
volume = {107},
number = {1},
pages = {e218227},
doi = {10.1212/WNL.0000000000218227},
pmid = {42314102},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/therapy ; *Cognitive Dysfunction/therapy ; Female ; Aged ; Male ; *Clinical Trials, Phase II as Topic ; Medical Futility ; Aged, 80 and over ; Longitudinal Studies ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: The cost and complexity of phase 2 randomized-controlled trials (RCTs) hinder further development of promising treatment candidates for Alzheimer disease (AD). The Simon Two-Stage futility trial design, originally developed for oncology, offers a streamlined approach to evaluate potential disease-modifying therapies by comparing single-arm outcomes with historical controls, but is predicated on identifying outcome measures that reliably worsen with the natural history of the disease, with minimal risk of improvement. We sought to determine the feasibility of such futility trials in AD-associated dementia and mild cognitive impairment (MCI) using a large prospective cohort.

METHODS: We analyzed longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive decline was assessed using AD Assessment Scale-Cognitive Subscale (ADAS-Cog 11 and ADAS-Cog 13), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Mini-Mental State Examination (MMSE) at 6, 12, and 24 months using different thresholds for worsening vs improvement. Binary logistic regression models examined baseline factors associated with cognitive worsening using different thresholds of worsening for each outcome of interest to assess what additional selection criteria may be needed for futility trials in AD-associated dementia vs MCI. Sample size estimates were derived based on expected rates of decline.

RESULTS: Among 2,665 participants (mean age 73.4 years [SD: 7.5], 1,260 [47.3%] female, 424 with AD-associated dementia), the CDR-SB exhibited the largest percentage of decline in AD-associated dementia and MCI, with 60.6% of patients with AD-associated dementia showing worsening when using a threshold of ≥1.0 points at 12 months vs 6.2% showing improvement. ADAS-Cog 11 and 13 showed similar decline patterns; for example, 41.7% with AD-associated dementia worsened by ≥ 5 points at 12 months on ADAS-Cog 13, whereas 5.8% improved. MMSE exhibited lower sensitivity; 25.8% with AD-associated dementia worsened by ≥ 5 points at 12 months, whereas 2.9% improved. Shorter trials (6-12 months) with 35-62 participants seemed feasible in AD-associated dementia, whereas MCI trials seemed to require 24 months and specific entry criteria based on age, apolipoprotein E ε4 status, and baseline CDR-SB performance.

DISCUSSION: Futility trials seem feasible in AD-associated dementia, offering a faster, cost-effective alternative to traditional phase 2 RCTs. CDR-SB seems to be the optimal primary outcome. Further validation in clinical trial data sets is warranted.},
}

Humans
*Alzheimer Disease/therapy
*Cognitive Dysfunction/therapy
Female
Aged
Male
*Clinical Trials, Phase II as Topic
Medical Futility
Aged, 80 and over
Longitudinal Studies
Cohort Studies

@article {pmid42314597,
year = {2026},
author = {Li, Y and Yang, XF and Yang, SY and Wang, L and Sun, YZ and Tan, WX and Yang, Z and Zheng, YZ and Wang, J and Jin, HW and Zeng, KW and Tu, PF},
title = {Millepurpan from Astragali Radix binds condensin SMC2 to reverse microglial cell cycle arrest and metabolic reprogramming in neuroinflammation.},
journal = {Bioorganic chemistry},
volume = {180},
number = {},
pages = {110089},
doi = {10.1016/j.bioorg.2026.110089},
pmid = {42314597},
issn = {1090-2120},
abstract = {Microglia are key immune cells in the central nervous system, whose dysfunction contributes to neuroinflammation and neurological disorders. Astragali Radix (AR), the root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, is known for neuroprotective effects, yet its active compounds remain underexplored. This study reports the first isolation of Millepurpan (MPP) from AR extract and reveals its potent anti-inflammatory effects in BV-2 microglial cells stimulated with lipopolysaccharide (LPS). Binding assays show MPP targets the ATPase head domain of structural maintenance of chromosomes 2 (SMC2), a condensin complex subunit, inducing steric hindrance that obstructs the ATP-binding pocket. LPS suppresses SMC2 nuclear translocation, causing p21-mediated G0/G1 arrest; MPP restores nuclear SMC2 and promotes G1/S transition. Seahorse metabolic analysis indicates MPP reverses LPS-induced glycolytic reprogramming, an effect abolished by Palbociclib co-treatment, highlighting cell cycle progression's role in metabolic regulation. In vivo, MPP crosses the blood-brain barrier, reduces microglial hyperactivation, and protects neurons in LPS-treated C57BL/6 mice. Immunofluorescence confirms MPP rescues nuclear SMC2 depleted by LPS, supporting its anti-neuroinflammatory action. Reanalysis of single-cell RNA sequencing datasets indicates dysregulation of SMC2 and downstream genes in Alzheimer's disease patients, suggesting SMC2 as a potential biomarker for neuroinflammation. Together, findings reveal an SMC2-mediated pathway whereby MPP binding promotes SMC2 nuclear translocation, mitigating neuroinflammation via regulation of microglial cell cycle and metabolic homeostasis. Given cell cycle regulation's importance in cellular homeostasis, SMC2 emerges as a promising therapeutic target, and MPP as a candidate agent for neuroinflammatory disorder treatment.},
}

@article {pmid42315374,
year = {2026},
author = {da Silva, AMP and de Siqueira Lima, DV and Figueiroa Souza, R and Lopes, VHP and Januario Campos Cardoso, L and Ornelas Pinto, EL and Gonçalves, OR and Braga, C and Cal, H and Haddad, DS and Vasconcelos, SMM and Duarte, FS and Perry, G and Anghinah, R},
title = {Cannabinoids Treatment for Agitation in Alzheimer's Disease: A Systematic Review and Meta-Analysis With Bayesian and Sequential Trial Analyses.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.05.016},
pmid = {42315374},
issn = {1545-7214},
abstract = {OBJECTIVE: Agitation and related neuropsychiatric symptoms are common in Alzheimer's disease (AD) and contribute to caregiver burden, functional decline, and institutionalization. Cannabinoid-based therapies have been investigated as potential symptomatic interventions, but evidence remains limited by small trials, heterogeneous formulations, and variable outcome reporting. We aimed to evaluate the efficacy, cognitive outcomes, and safety of cannabinoid-based therapies in AD.

METHODS: This systematic review and meta-analysis were prospectively registered in PROSPERO and conducted following PRISMA 2020 guidelines. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched through April 2025 for randomized placebo-controlled trials evaluating cannabinoid-based therapies for agitation or neuropsychiatric symptoms in AD. One nonrandomized open-label study was retained as supplementary evidence for sensitivity analyses. Primary efficacy analyses were restricted to randomized between-group contrasts. Outcomes included Neuropsychiatric Inventory (NPI) total score, Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF), NPI agitation/aggression, Mini-Mental State Examination (MMSE), and safety outcomes. Random-effects meta-analyses were complemented by Bayesian models and Trial Sequential Analysis.

RESULTS: Seven studies met the inclusion criteria, including six randomized trials and one open-label prospective cohort, with 221 participants enrolled. Cannabinoid-based therapies showed lower neuropsychiatric symptom and agitation scores than placebo in randomized between-group analyses: NPI total score (standardized mean difference [SMD], -0.31; 95% confidence intervals [CI], -0.47 to -0.15; k = 4), CMAI-SF (SMD, -0.40; 95% CI, -0.69 to -0.10; k = 3), and NPI agitation/aggression (SMD, -0.47; 95% CI, -0.69 to -0.25; k = 3). Bayesian posterior probabilities for lower symptom scores exceeded 95%. MMSE findings did not support a consistent cognitive benefit. Somnolence was the principal safety signal (risk ratios, 2.25; 95% CI, 1.43-3.54), with Trial Sequential Analysis suggesting sufficient accrued information for this outcome. Falls and fatigue were imprecisely estimated.

CONCLUSIONS: Cannabinoid-based therapies showed lower agitation and neuropsychiatric symptom scores than placebo in AD, with somnolence as the main safety concern. Interpretation remains limited by few trials, heterogeneous formulations and outcome instruments, short follow-up, and concentrated statistical weight. Larger randomized trials with formulation-specific protocols, longer follow-up, active comparators, and systematic safety monitoring are needed.},
}

@article {pmid42315445,
year = {2026},
author = {Yassine, HN and Pour, SG and Juarez, M and Arrelanas, IC and Ali, N and Dikeman, D and Sanchez, A and Park, J and Kerman, B and Duro, MV and Asante, I and Louie, S and Kono, N and D'Orazio, LM and Chui, H and Mack, WJ and Harrington, MG and Braskie, MN and Schneider, LS},
title = {CNS target engagement of high-dose DHA supplementation in older adults at risk for dementia: a randomised, double-blind, placebo-controlled trial.},
journal = {EBioMedicine},
volume = {},
number = {},
pages = {106316},
doi = {10.1016/j.ebiom.2026.106316},
pmid = {42315445},
issn = {2352-3964},
abstract = {BACKGROUND: APOE ε4 carriers have increased Alzheimer's disease risk and altered omega-3 metabolism. No large-scale prevention trials have tested high-dose docosahexaenoic acid (DHA) supplementation specifically in non-demented APOE ε4 carriers with low baseline omega-3 intake for early intervention.

METHODS: We conducted a phase IIa 24-month, randomised, double-blind, placebo-controlled trial (NCT03613844) at the University of Southern California between September 2018 and May 2024. Participants aged 55-80 years without dementia, low dietary DHA intake (<200 mg/day), and ≥1 dementia risk factor were stratified by cerebrospinal fluid (CSF) collection willingness into lumbar puncture (LP) or no-LP arms. Within each arm, participants were randomised 1:1 to receive 2 g/day DHA or placebo, stratified by APOE ε4 status. Primary outcome was the 6-month CSF DHA-to-arachidonic acid (AA) ratio change. Secondary and exploratory outcomes included 24-month neuroimaging and cognitive measures.

FINDINGS: Of 739 screened individuals, 365 participants were randomised (181 LP arm, 184 no-LP arm). Mean age was 66.4 years (SD 5.7), 210 (58%) were female, 142 (39%) were Hispanic, 173 (47%) were APOE ε4 carriers. DHA supplementation increased CSF DHA/AA ratio at 6 months vs placebo (0.17 [95% CI 0.15-0.18] vs -0.02 [95% CI -0.04 to -0.0004]; difference 0.19 [95% CI 0.16-0.21]; p < 0.0001), independent of APOE ε4 status (interaction p = 0.71). Dropout was 38%, mainly due to COVID-19. No treatment differences were observed in brain volumes or cognitive performance over 24 months. Adverse events were comparable between groups, with no serious adverse events attributed to treatment.

INTERPRETATION: High-dose DHA achieved CNS target engagement in non-demented older adults with low baseline omega-3 intake, independent of APOE ε4. Despite biochemical target engagement, no differences in cognition or brain structure were observed over 24 months. Future research should prioritise brain DHA metabolism over further supplementation trials.

FUNDING: National Institute on Aging (R01AG057684) and the ADDF (GC-201711-2014197).},
}

@article {pmid42315518,
year = {2026},
author = {Dar, NJ and Soriano-Castell, D and Maher, P},
title = {Sustained dysregulation of iron and glutathione homeostasis induces chronoferroptosis, a persistent ferroptotic adaptation in neuronal cells.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03208-6},
pmid = {42315518},
issn = {2058-7716},
support = {R01AG067331//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01AG069206//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; },
abstract = {Although iron accumulates in brain regions impacted by neurodegenerative diseases such as Alzheimer's and Parkinson's, how chronic elevated iron levels contribute to neuronal dysfunction remains unclear. Here, we show that sustained iron overload, but not acute exposure, leads to a state of ferroptotic stress where nerve cells remain viable but become hypersensitive to oxidative injury. Retinoic acid-differentiated SH-SY5Y neuronal cells were exposed to acute (6-8 h) or chronic (9 days) iron loading to model transient versus prolonged age-related iron stress. While acute iron exposure produced minimal biochemical changes and did not sensitize cells to oxidative or ferroptotic challenges, chronic iron exposure induced ferritin upregulation, mitochondrial superoxide accumulation, suppression of GPX4 expression, elevated lipid peroxidation and loss of cellular glutathione (GSH). In addition, chronic but not acute GSH depletion by buthionine sulfoximine (BSO) recapitulated the iron-induced phenotype. Cells under chronic ferroptotic stress exhibited increased sensitivity not only to the ferroptosis inducer RSL-3 but also to hydrogen peroxide. Ferrostatin-1 significantly mitigated these effects suggesting that lipid peroxidation drives this state. Together, these findings demonstrate that, in contrast with acute exposure, chronic disruption of iron homeostasis with consequent GSH depletion remodels cellular redox homeostasis over time, inducing a state we term chronoferroptosis: a persistent ferroptotic adaptation characterized by coordinated alterations in iron-handling and antioxidant defense proteins that may represent early vulnerability to neurodegenerative pathology. Thus, these studies highlight the importance of sustained stress paradigms for modeling the progressive nature of neurodegenerative diseases.Graphical abstract illustrating how prolonged iron or BSO exposure drives a persistent ferroptotic stress state in RA differentiated SH-SY5Y cells. These cells were subjected to either acute exposure for 6-8 h or chronic exposure for 9 days. Acute iron or BSO treatment caused minimal biochemical changes and did not increase vulnerability to oxidative or ferroptotic challenges. In contrast, chronic exposure stimulated ferritin production, mitochondrial superoxide buildup, GSH depletion, reductions in GPX4 expression and increased lipid peroxidation without altering cell viability. However, these chronically stressed neuronal cells became markedly more sensitive to secondary stressors such as RSL-3 or hydrogen peroxide resulting in decreases in cell viability, whereas viability was not altered in acutely treated cells.},
}

@article {pmid42316324,
year = {2026},
author = {Figueiredo, EV and Azevedo, CV and Penitente, AR and Pedrosa, VR and Camilo da Silva, VR and Longo, BM},
title = {Impact of sex differences on microglial function in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02099-0},
pmid = {42316324},
issn = {1758-9193},
support = {2022/00249-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 312904/2021-5//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
abstract = {Aging is the strongest risk factor for Alzheimer's disease (AD), a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology (hyperphosphorylated tau and neurofibrillary tangles [NFTs]), and associated neuroinflammatory processes. Age-related cellular and molecular stressors, including mitochondrial dysfunction, genomic instability, and chronic low-grade inflammation, progressively increase vulnerability to neurodegeneration. In parallel, sex is increasingly recognized as a biological variable that shapes AD risk, clinical course, and neuropathological burden. Women account for roughly two-thirds of AD cases, a disparity not fully explained by longevity. Multiple factors likely contribute, including hormonal transitions across the lifespan (particularly menopausal estrogen decline), sex chromosome-linked immune regulation, sex-dependent interactions between genetic risk factors (e.g., APOE4 and TREM2) and brain aging, and differences in vascular risk, cognitive reserve, and sociocultural exposures that influence disease expression and detection. Microglia, the brain's resident immune cells, are sexually dimorphic, and respond to Aβ and tau pathology, modulating inflammatory signaling, synaptic remodeling, and neurovascular dysfunction implicated in AD. Emerging human and experimental evidence indicate that microglial activation states, immunometabolism, and functional responses differ between males and females and may contribute to sex-specific AD trajectories. Here, we synthesize current evidence supporting microglial sexual dimorphism across aging and AD, highlight possible candidates (hormonal signaling, immuno-aging, disease-associated microglial states, and immunometabolic remodeling), and discuss key knowledge gaps toward sex-informed precision approaches for prevention and treatment.},
}

@article {pmid42316357,
year = {2026},
author = {Ma, L and Geng, Y and Wang, L and Zhang, G and Xu, S and Wang, Z},
title = {Rational Design of Sequentially Activated Dual-Locked Near-Infrared Fluorescent Probe for Simultaneous Imaging of Cerebral Amyloid-β Plaques and ClO[-] in Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.6c01603},
pmid = {42316357},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder mediated by multiple pathological factors, including amyloid-β (Aβ) plaque deposition and oxidative stress. Herein, we report a new class of sequentially activated dual-lock-responsive fluorescent probes, D-BDY and T-BDY, which were designed by integrating pyrrole-based electron-donating units and molecular rotors into the BODIPY scaffold. This strategic design enabled photoinduced electron transfer (PET) and twisted intermolecular charge transfer (TICT) modulated fluorescence responses to both Aβ1-42 aggregates and hypochlorite (ClO[-]). The probes exhibited remarkable fluorescence enhancement (50-100-fold) when exposed to a mixed solution containing both ClO[-] and Aβ1-42 aggregates. Confocal imaging and staining of Aβ-containing brain slices revealed that the probes preferentially bind to the dense β-sheet-rich cores of plaques, and their colocalization with thioflavin-T (ThT) was further enhanced following ClO[-] activation. Furthermore, in vivo imaging in an APP/PS1 transgenic AD mouse model demonstrated that D-BDY successfully crossed the blood-brain barrier (BBB), enabling real-time monitoring of Aβ1-42 plaques and the oxidative microenvironment. The observed fluorescence intensity exhibited a strong correlation with pathological severity and was significantly attenuated upon antioxidant treatment. These results established D-BDY as a promising single-molecule dual-locked fluorescent probe capable of sensitively visualizing Aβ1-42 aggregation and ClO[-]-related oxidative stress in vivo, offering a valuable tool for AD diagnosis and pathological progression monitoring.},
}

@article {pmid42317872,
year = {2026},
author = {Singh, G and Singh, G and Shreya, and Kumari, A and Aran, KR},
title = {Nutrients and bioactive compounds as modifiers of neurodegenerative trajectories: molecular mechanisms, translational barriers, and precision nutrition.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1819432},
pmid = {42317872},
issn = {2296-861X},
abstract = {The Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS) are a growing health burden across the world with minimal disease-modifying treatment and therapy. It is emerging that neurodegeneration is not only a progressive loss of neurons, but also a nutrient-sensitive systems-level dysfunction that takes the form of redox imbalance, chronic neuroinflammation, mitochondrial dysfunction, impaired proteostasis, and synaptic loss. The aging brain are more prone to metabolic vulnerability, and subclinical deficiencies in essential nutrients and bioactive dietary compounds may exacerbate cellular stress responses that contribute to disease progression. It summarizes the existing data on the effects of nutrients like vitamins, minerals, polyunsaturated fatty acids, and various phytochemicals in modulating neuronal homeostasis by regulating oxidative signaling, inflammatory cascades, mitochondrial resilience, autophagy, and synaptic plasticity. These nutrient-mediated effects collectively influence neuronal survival, synaptic integrity, and cognitive function by affecting disease susceptibility and progression. Additionally newer metabolites of the marine and microbiome act as new neuroactive agents. The evidence from in-vitro and preclinical models, translation to clinical benefit remains inconsistent due to heterogeneity in study design, bioavailability, blood- brain barrier penetration, dosing strategies and disease stage. This review highlights emerging potential of precision nutrition frameworks that integrate nutrigenomics, metabolomics, and microbiome interactions, and individualized metabolic profiling to enable context-dependent and stage-specific interventions. Moreover, conceptualizing neurodegeneration as a nutrient-sensitive, systems level disorder, propose a mechanistically informed and integrative approach that combine targeted nutritional strategies with pharmacological and lifestyle therapies to more effectively modify neurodegenerative trajectories.},
}

@article {pmid42317884,
year = {2026},
author = {Azinge, N and Elkomi, R and Bisrat, M and Gillani, SF and Deverapalli, M and Beyene, E and Michael, MB and Deonarine, A},
title = {Proton Pump Inhibitors Versus H2 Blockers and the Risk of Incident Dementia in Adults Younger Than 65.},
journal = {Cureus},
volume = {18},
number = {5},
pages = {e109101},
pmid = {42317884},
issn = {2168-8184},
abstract = {BACKGROUND: Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2 blockers) are routinely prescribed for the long-term management of chronic acid-related gastrointestinal conditions. Although prior research has explored a potential link between PPI exposure and cognitive decline, findings across studies have been inconsistent, and most investigations have concentrated on elderly populations.

OBJECTIVE: This study aimed to evaluate whether PPI therapy, relative to H2 blocker therapy, was associated with differential incident dementia risk among adults below the age of 65 who carry diagnoses warranting sustained acid suppression.

METHODS: A retrospective cohort analysis was performed using data from the TriNetX Global Collaborative Network. Eligible participants were adults aged 18-65 with a confirmed diagnosis of gastroesophageal reflux disease with esophagitis (ICD-10-CM K21.0) or Barrett's esophagus (ICD-10-CM K22.7), and documented treatment with either a PPI (ATC code A02BC) or an H2 blocker (ATC code A02BA). All individuals with pre-existing dementia were excluded. Cohorts were balanced via 1:1 propensity score matching on age, sex, and baseline psychiatric and neurodevelopmental diagnoses. The main outcome, incident dementia, was captured through ICD-10 diagnostic codes encompassing Alzheimer's disease (G30), dementia secondary to other diseases (F02), unspecified dementia (F03), and other degenerative nervous system disorders (G31). Analyses included risk ratios, odds ratios, Kaplan-Meier survival curves, and Cox proportional hazards regression.

RESULTS: Following propensity score matching, each treatment group comprised 197,187 patients. New-onset dementia was recorded in 368 individuals (0.19%) assigned to the PPI group and 607 individuals (0.31%) in the H2 blocker group. Relative to H2 blocker use, PPI therapy was linked to a meaningfully lower likelihood of developing dementia (risk ratio 0.61, 95% CI 0.53-0.69; odds ratio 0.61, 95% CI 0.53-0.69). Kaplan-Meier analyses corroborated these findings, with a significantly reduced dementia hazard observed among PPI-treated patients (hazard ratio 0.63, 95% CI 0.55-0.72; log-rank p < 0.001).  Conclusion: In this propensity-matched sample of adults younger than 65 years with chronic acid-related diagnoses, PPI therapy did not elevate the risk of incident dementia relative to H2 blockers and was, in fact, associated with a statistically lower observed risk. These results should reassure clinicians and patients regarding the cognitive safety profile of PPIs when sustained acid suppression is medically necessary.},
}

@article {pmid42307825,
year = {2026},
author = {Li, Y and He, X},
title = {Single-cell Transcriptomics Reveals that the SORBS1/FBXO22/BAG3 Axis Drives Astrocyte Senescence via Calcium Signaling and Affects Alzheimer's Disease-Related Neuronal Damage.},
journal = {Neuromolecular medicine},
volume = {28},
number = {1},
pages = {},
pmid = {42307825},
issn = {1559-1174},
mesh = {*Astrocytes/pathology/metabolism/physiology ; *Alzheimer Disease/pathology/metabolism/genetics ; *Cellular Senescence/genetics ; Humans ; *Neurons/pathology ; *Calcium Signaling/physiology/genetics ; *Adaptor Proteins, Signal Transducing/physiology/genetics ; Amyloid beta-Peptides/pharmacology/toxicity ; *Inhibitor of Apoptosis Proteins/physiology/genetics ; Animals ; Single-Cell Analysis ; Coculture Techniques ; Senescence-Associated Secretory Phenotype/genetics ; Single-Cell Gene Expression Analysis ; Cells, Cultured ; *Nerve Tissue Proteins/physiology/genetics ; Ubiquitination ; Transcriptome ; },
abstract = {In Alzheimer's disease (AD), senescent astrocytes fuel neuroinflammation and neuronal damage via the senescence-associated secretory phenotype (SASP). Calcium signaling plays a crucial role in this process, but the underlying molecular mechanisms remain elusive. We retrieved scRNA-seq data from the Gene Expression Omnibus (GEO) for AD and control brains. After cell-type annotation, we resolved astrocyte sub-clusters. Pseudotime trajectory and differential-expression analyses identified SORBS1 as a key senescence-related gene, which we followed with gene-set enrichment analysis. Next, we established an in vitro AD model by treating astrocytes with amyloid-β (Aβ). We evaluated astrocyte senescence using SA-β-gal staining, qRT-PCR, Western blot (WB) for senescence markers, and ELISA for SASP cytokines. We measured concentration of Ca[2+] with Fluo-4 AM probes. Subsequently, bioinformatic screening predicted FBXO22 as an interactor of SORBS1 and BAG3 as a ubiquitination substrate of FBXO22. We validated these interactions using Co-IP and in vitro ubiquitination assays. Finally, we constructed an astrocyte-neuron co-culture model. We detected neuronal cell viability, AChE activity, AD phenotype-related protein expression, apoptosis, and levels of inflammatory factors using MTT assay, specific kits, WB, flow cytometry, and ELISA, respectively, to assess neuronal damage. ScRNA-seq analysis revealed a marked reduction in astrocyte expression in AD brains, which may result from cellular senescence. The SASP gene SORBS1 was selectively up-regulated in astrocytes and significantly enriched in calcium-signaling pathways. Functional assays confirmed that SORBS1 accelerated astrocyte senescence. Mechanistically, SORBS1 interacted with FBXO22 to promote the ubiquitin-dependent degradation of BAG3, thereby amplifying calcium signaling, accelerating astrocyte senescence, and contributing to AD-related neuronal damage. We uncover a novel mechanism by which the SORBS1/FBXO22/BAG3 axis drives astrocyte senescence through the regulation of calcium signaling, thereby influencing AD-related neuronal damage. This finding provides a potential therapeutic target for AD treatment by targeting astrocyte senescence.},
}

*Astrocytes/pathology/metabolism/physiology
*Alzheimer Disease/pathology/metabolism/genetics
*Cellular Senescence/genetics
Humans
*Neurons/pathology
*Calcium Signaling/physiology/genetics
*Adaptor Proteins, Signal Transducing/physiology/genetics
Amyloid beta-Peptides/pharmacology/toxicity
*Inhibitor of Apoptosis Proteins/physiology/genetics
Animals
Single-Cell Analysis
Coculture Techniques
Senescence-Associated Secretory Phenotype/genetics
Single-Cell Gene Expression Analysis
Cells, Cultured
*Nerve Tissue Proteins/physiology/genetics
Ubiquitination
Transcriptome

@article {pmid42307826,
year = {2026},
author = {Soni, S and Sarkar, S and Tripathi, P and Maurya, S and Kaur, G and Haque, S},
title = {Neuroinflammation mediated repurposing of clemastine for Alzheimer's disease through network pharmacology, molecular dynamics, and experimental validation studies.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42307826},
issn = {1568-5608},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with significant involvement of neuroinflammation, for which the current interventions are limited in efficacy. Certain antihistamines such as clemastine have neuroprotective properties beyond H1 receptor antagonism, including anti-inflammatory, antioxidant, remyelinating effects, modulates neuroinflammatory pathways. This study aims to investigate the neuroprotective potential of clemastine via in silico and in vivo studies for repurposing against AD.

METHODOLOGY: In silico analyses involved network pharmacology, molecular docking, and 100-ns molecular dynamic simulations along with principal component analysis and binding free energy calculations. Whereas, experimental studies involved treatment of clemastine (5 mg/kg and 10 mg/Kg, p.o.) for 14 days in lipopolysaccharide-induced neuroinflammatory (250 µg/Kg, i.p.) rat. Behavioral assessment was performed using Morris water maze (MWM) test. Biochemical parameters including acetylcholinesterase (AChE) activity, oxidative stress markers (MDA, SOD, CAT, GSH), and inflammatory biomarkers (NLRP3, TNF-α, IL-1β) were evaluated. Histopathological analysis of hippocampal CA3 region was performed using Nissl's staining.

RESULTS: Network analysis identified 52 overlapped targets between clemastine and AD. Hub genes such as GSK3β, DRD1, DRD2, CHRNA4, and SLC6A4 were associated with neurotransmission and kinase signaling pathways. Enrichment analysis highlighted PI3K/Akt, MAPK, and neuroactive ligand-receptor interaction pathways. Molecular docking and molecular dynamic simulations confirmed stable binding of clemastine with GSK-3β, PI3K, and NLRP3 proteins. Animal model studies demonstrated that clemastine significantly improved cognitive performance in MWM (p < 0.001), reduced AChE level (p < 0.0001), restored antioxidant enzyme levels, suppressed inflammatory mediators (p < 0.0001), and preserved hippocampal neuronal structure.

CONCLUSION: The study provides novel integrative evidence linking its antihistaminic action with simultaneous regulation of neuroinflammation through multi-target modulation of inflammation, oxidative stress, and neuronal signaling pathways, highlighting its potential as a promising repurposed therapeutic candidate for AD.},
}

@article {pmid42307833,
year = {2026},
author = {Sood, S and Singh, S and Singh, TG},
title = {PCSK9 in bridging metabolism and neurodegeneration: a new paradigm for alzheimer's treatment.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42307833},
issn = {1573-7365},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Proprotein Convertase 9/metabolism ; Animals ; Cholesterol/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; *Nerve Degeneration/metabolism ; },
abstract = {Proprotein convertase subtilisin-kexin type 9 (PCSK9) has recently emerged as a significant mediator that links metabolic dysfunction to neurodegeneration related to Alzheimer's disease (AD). It is a well-known and crucial component involved in cholesterol homeostasis. However, its function in the central nervous system (CNS) is still in its early stages. Normally, it is engaged with the breakdown of cholesterol in the body, but within the brain, PCSK9 has been seen to disrupt the homeostasis of cholesterol and its uptake. Receptors such as LDL receptor-related protein-1 (LRP-1) and low-density lipoprotein receptor (LDLR) are crucial for the survival of neurons, as they are responsible for the clearance of amyloid-β (Aβ) and peripheral lipid control. Elevated PCSK9 activity may promote degradation of these receptors, which eventually leads to deposition of Aβ near synapses along with reduced uptake of cholesterol by neurons, which may contribute to neurotoxicity and neuronal dysfunction. This review aims to explore the effect of elevated PCSK9 levels on the development as well as exacerbation of AD via different molecular mechanisms. Along with cholesterol dyshomeostasis, PCSK9 is found to be involved in glucose dysregulation, mechanistic target of rapamycin (mTOR) dysregulation, increased oxidative stress, neuroinflammation, reduced neurogenesis, affected Wnt-β-catenin signaling, and cholinergic signaling. Together, these mechanisms may contribute to AD progression. Preclinical studies show that pharmacological therapies targeting PCSK9 can give promising results by reducing neuroinflammation, modulating lipid homeostasis, and lowering Aβ accumulation. Therefore, modulation of PCSK9 represents a promising therapeutic strategy that warrants further mechanistic and clinical investigation in AD.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
*Proprotein Convertase 9/metabolism
Animals
Cholesterol/metabolism
Amyloid beta-Peptides/metabolism
*Brain/metabolism
*Nerve Degeneration/metabolism

@article {pmid42308766,
year = {2026},
author = {Kam, MK and Kim, JW and Choi, JY and Koh, YH and Jo, C},
title = {HSP90 is involved in curcumin-mediated inhibition of tau aggregation.},
journal = {Biochemical and biophysical research communications},
volume = {829},
number = {},
pages = {154140},
doi = {10.1016/j.bbrc.2026.154140},
pmid = {42308766},
issn = {1090-2104},
abstract = {Tau aggregation in neurons is a pathological hallmark of Alzheimer's disease (AD). The development of therapeutic drugs that inhibit tau aggregation in tauopathies, including AD, remains challenging. Herein, we developed a tau self-interaction reporter system using split Nanoluciferase (Tau-NLuc) in which luciferase activity is restored by the self-assembly of split Nanoluciferases following self-interaction between tau proteins. Curcumin (CCM), a phenolic organic compound, significantly reduced luciferase activity in the Tau-NLuc system, including mutant tau forms such as S396/404E and P301L, which are known aggregation-prone tau forms, suggesting that CCM may act as a potential inhibitor of tau aggregation. CCM did not alter the protein levels of phosphorylated tau as well as total tau, indicating that the reduction in luciferase activity by CCM did not originate from tau degradation, but rather from tau aggregation inhibition. Of note, CCM significantly increased heat shock protein (HSP) 90 dimer. The reduced luciferase activity in the Tau-NLuc system by CCM was recovered by knockdown of the HSP90 gene using a siRNA specific for HSP90 or treatment of an inhibitor of HSP90 NCT-58, supporting the involvement of HSP90. Intriguingly, hexahydrocurcumin (HHC), a derivative of CCM, did not reduce luciferase activity, nor did it induce the formation of the HSP90 dimer, suggesting that HSP90 dimer formation may contribute to the CCM-mediated inhibition of tau aggregation. Taken together, the results demonstrate that CCM inhibits tau aggregation with the involvement of HSP90, providing novel insights into the development of therapeutic strategies for AD.},
}

@article {pmid42309020,
year = {2026},
author = {Milà-Alomà, M and Hausle, I and Petersen, KK and Thropp, P and Schindler, SE and Tosun, D and , },
title = {The time interval from amyloid to tau PET positivity varies by age, sex and APOE-ε4 status.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100622},
doi = {10.1016/j.tjpad.2026.100622},
pmid = {42309020},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials.

OBJECTIVES: To investigate how the estimated age at amyloid and tau PET positivity, and the time interval between these two key events ("amyloid-tau time interval"), relate to symptom onset and clinical progression, and to assess the effects of APOE-ε4 status and sex on these associations.

DESIGN: This analysis used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Harvard Aging Brain Study (HABS).

SETTING: The ADNI is a multicenter observational cohort conducted at 55 sites across the United States; The HABS is a longitudinal, single-center observational cohort.

PARTICIPANTS: This study included participants with at least one positive amyloid PET scan (ADNI n = 792; HABS n = 104) or at least one positive tau PET scan (ADNI n = 212; HABS n = 48). All participants had information on sex, APOE-ε4 status, and longitudinal cognitive assessments.

MEASUREMENTS: We examined the influence of APOE-ε4 status, sex, and their interaction on the estimated age at biomarker positivity and the amyloid-tau time interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset (CDR > 0) based on estimated biomarker positivity age and the amyloid-tau time interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline, as measured by CDR-SB, over five years following symptom onset according to estimated biomarker positivity age and amyloid-tau time interval. Additional models included interaction terms with sex or APOE-ε4 status.

RESULTS: The amyloid-tau time interval varied markedly between individuals and was shorter in APOE-ε4 carriers, women, and those with older age at amyloid PET positivity. APOE-ε4 carriers and women became amyloid and tau PET positive at younger ages. Following amyloid PET positivity, a shorter time to tau PET positivity predicted earlier symptom onset. After symptom onset, faster cognitive decline was observed in individuals with younger ages at amyloid or tau PET positivity. The time to symptom onset following tau PET positivity, or the rate of cognitive decline after symptom onset, were not influenced by the amyloid-tau time interval.

CONCLUSIONS: After becoming amyloid PET positive, APOE-ε4 carriers, women and older individuals may have a shorter window for detection and treatment before they become tau PET positive and develop symptoms. These findings should guide the identification of individuals at highest risk of rapid AD progression, enabling more efficient participant selection for clinical trials.},
}

@article {pmid42309609,
year = {2026},
author = {Mia, M and Dutta, A and Hossain, MM and Adhikari, J and Rahman, MM and Shibly, AZ},
title = {Exploring the neuroprotective, antioxidant, and anti-amyloid effects of Ganoderma lucidum compounds in Alzheimer's disease: insights from experimental and computational approaches.},
journal = {Journal, genetic engineering & biotechnology},
volume = {24},
number = {2},
pages = {100706},
pmid = {42309609},
issn = {2090-5920},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation and oxidative stress, with limited effective therapeutic options. This study evaluated the antioxidant, neuroprotective, and anti-amyloidogenic potential of Ganoderma lucidum, medicinal mushroom rich in bioactive compounds, including triterpenoids and sterols. Antioxidant activity was assessed using the DPPH assay, and neuroprotective effects were examined in Caenorhabditis elegans models (N2 and CL4176). The anti-Aβ potential of selected bioactive compounds was investigated through molecular docking, molecular dynamics simulations, and MM/GBSA analysis, along with ADMET predictions. The extract exhibited strong antioxidant effects, achieving 96.3% scavenging at 0.25 mg/mL. In C. elegans, treatment enhanced survival under oxidative stress by 25% at 0.5 mg/mL (p < 0.01) and delayed Aβ-induced paralysis, with 17.82% of worms remaining active at 68 h. Docking studies identified Epoxyganoderiol C (-7.8 kcal/mol), 5,6-Dihydroergosterol (-7.9 kcal/mol), and Ganoderiol A (-7.7 kcal/mol) as potent Aβ inhibitors, stabilized in molecular dynamics simulations with favorable RMSD, RMSF, Rg, and SASA profiles. MM/GBSA analysis confirmed strong binding affinities for 5,6-Dihydroergosterol, Epoxyganoderiol C, and Ganoderiol A against Aβ, with ΔG_bind values of - 71.66, -56.42, and - 45.45 kcal/mol, respectively. ADMET predictions indicated good drug-likeness, high gastrointestinal absorption, and no toxicity risks. In conclusion, G. lucidum extract demonstrated potent antioxidant and neuroprotective effects, while its bioactive key compounds-Epoxyganoderiol C, 5,6-Dihydroergosterol, and Ganoderiol A-showed favorable binding affinity and stability with Aβ, along with acceptable pharmacokinetic profiles. These findings suggest that G. lucidum and its bioactive constituents may serve as promising natural candidates for AD therapy.},
}

@article {pmid42310298,
year = {2026},
author = {Diaz Escarcega, R and M J, VK and Arizmendez, A and Tan, C and Urayama, A and Marrelli, SP and Morales, R and Wefel, JS and Zhang, C and McCullough, LD and Kim, N and Monchaud, D and Jung, SY and Tsvetkov, AS},
title = {Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08971-z},
pmid = {42310298},
issn = {2041-4889},
support = {4R01AG068292//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AFAR BIG21042//Glenn Family Foundation/ ; AFAR BIG21042//American Federation for Aging Research (American Federation for Aging Research, Inc.)/ ; },
abstract = {G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in male and female neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.},
}

@article {pmid42310327,
year = {2026},
author = {Varga, BT and Ernyey, AJ and Tajti, BT and Gáspár, A and Demeter, Z and Kollár, L and Kovács, P and Albert, M and Alpár, A and Gyertyán, I},
title = {Translational difficulties in establishing a pharmacologically induced neurovascular uncoupling model in rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-58244-0},
pmid = {42310327},
issn = {2045-2322},
abstract = {Neurovascular uncoupling (NVU) contributes to neurological disorders like Alzheimer's disease. While a mouse NVU model exists, a reliable rat model critical for cognitive research remains underdeveloped. To address this methodological gap, we investigated a pharmacological approach in rats using the same drugs (N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH), L-NG-nitroarginine methyl ester (L-NAME), indomethacin) that proved to be efficacious in mice. The compounds were formulated as a cocktail solution and administered intraperitoneally for 13 days to aged, cognitively experienced Long-Evans rats. Our goal was to induce NVU while minimizing adverse systemic effects seen previously (e.g., hypertension, intestinal ulceration). The treatment induced only a modest (28%, non-significant) reduction in cerebral hyperaemia, with decreased prostaglandin E2 levels but unchanged 11,12-epoxyeicosatrienoic acid concentration in the brain. Cognitive effects were limited-transient impairment in the 5-choice task but no changes in spontaneous alternation, visual discrimination, cooperation, or motor learning. Significant adverse effects emerged: reduced food intake, weight loss, gastrointestinal malaise, and moderate renal toxicity. Our findings specifically highlight the challenges of achieving sufficient and symptomatically apparent NVU while minimizing systemic toxicity. While partial NVU occurred, this polypharmacy approach had major limitations. A reliable, industrially applicable rat NVU model remains urgently needed to accelerate antidementia drug development.},
}

@article {pmid42311340,
year = {2026},
author = {Li, G and Jiao, S and Zhou, Y and Cheng, X},
title = {Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: theoretical foundations, regulatory suspension, and translational challenges.},
journal = {Frontiers in aging},
volume = {7},
number = {},
pages = {1849207},
pmid = {42311340},
issn = {2673-6217},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological changes in β-amyloid protein deposition, abnormal tau protein phosphorylation neurofibrillary tangles, and chronic neuroinflammation. Recent studies have shown that the glymphatic-meningeal-cervical lymphatic system pathway plays a crucial role in the clearance of intracranial metabolic waste. Dysfunction of this system may lead to a decrease in the clearance efficiency of Aβ and tau proteins. Deep cervical lymphaticovenous anastomosis (DCLVA) has been proposed as a novel surgical approach to enhance cervical lymphatic drainage, reduce Aβ/tau accumulation, and improve cognitive function in patients with AD. However, on 8 July 2025, the National Health Commission of China issued a notice prohibiting the clinical application of "deep cervical lymphaticovenous anastomosis" for the treatment of AD. This article provides a narrative review with critical appraisal of the theoretical basis, surgical mechanisms, and clinical evidence of DCLVA for AD. We objectively evaluate the strengths and limitations of current clinical studies, critically appraise the uncertainty of underlying physiology, and comprehensively analyze the potential risks, safety concerns, and translational obstacles that led to regulatory suspension. We further clarify unresolved scientific questions including pressure gradients, lymphatic contractility, reflux risk, anastomotic patency, and biomarker validation. By framing DCLVA within the context of its clinical prohibition, we provide clinicians and researchers with a balanced appraisal that acknowledges both the procedure's potential and the substantial gaps that must be addressed before widespread application can be justified.},
}

@article {pmid42299852,
year = {2026},
author = {Beh-Pajooh, A},
title = {Identification of candidate diagnostic biomarkers and gene networks for moderate stages of Alzheimer's disease in fusiform gyrus exhibiting neurofibrillary tangles.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452277},
doi = {10.1177/13872877261452277},
pmid = {42299852},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder whose incidence grows with age and its development is gradual. However, if detected earlier there is much hope to prevent further exacerbation. In this study, NGS transcriptomics data from cases and controls with Braak scores of III-IV were investigated that all possessed neurofibrillary tangles (NFTs) in their fusiform gyrus.ObjectiveThe aim of this study was to discover the underlying mechanisms at gene level which could explain cognitive impairment by considering the presence of NFTs in both groups.MethodsDifferentially expressed genes (DEGs) were determined and ROC AUC were evaluated by leave-one-out cross-validation method on the diagnostic DEGs to detect candidate gene biomarkers. WGCNA was employed to identify co-expression modules with their trait association. Finally, in silico hybridization of lncRNAs from potential biomarkers with important AD-related microRNAs was carried out.ResultsHighly ranked potential diagnostic gene biomarkers revealed assessed AUC ranges of 80-90% in which RASGRF2-AS1 demonstrated the highest value. WGCNA demonstrated upregulated genes in favor of dephosphorylation of tau, proper proteostasis and vascular health in resilient controls whereas dysfunctional proteostasis, chronic protein misfolding, heightened cellular stress and tetrahydrobiopterin deficiency were attributed to cognitive impairment in AD patients. In silico analyses predicted some lncRNAs with a high possibility of acting as sponge for AD-related microRNAs.ConclusionsThis study discovered potential diagnostic gene biomarkers and transcriptional signatures that could explain the mechanisms of cognitive decline by considering the existence of NFTs, which could provide further insight for diagnosis and treatment of the disease.},
}

@article {pmid42300138,
year = {2026},
author = {Wolf, EJ and Zhao, X and Hao, S and Lawhorn, C and Carbaugh, J and Fortier, CB and Milberg, WP and Logue, MW and Miller, MW},
title = {PTSD Severity-Related Accelerated Aging, Hippocampal Volume, and CLDN5 DNA Methylation.},
journal = {Biopsychosocial science and medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/PSY.0000000000001501},
pmid = {42300138},
issn = {2998-8756},
abstract = {OBJECTIVE: The claudin-5 (CLDN5) gene is critical for blood brain barrier integrity and may link traumatic stress, accelerated aging, and neurological disease. Building on prior research showing associations between trauma exposure and PTSD with CLDN5 DNA methylation (DNAm), we tested if candidate CLDN5 DNAm loci were associated with advanced epigenetic aging in blood and brain tissue and with hippocampal volume.

METHODS: 1302 trauma-exposed individuals (Mage=44.23, SD=13.71; 76% male) underwent psychiatric diagnostic interviews and blood draws for obtaining epi/genetic information; 473 underwent magnetic resonance imaging of the brain. Data from 109 PTSD brain bank decedents with DNAm from ventromedial prefrontal cortex (vmPFC) were also examined (Mage-at-death=45.20, SD=14.21; 62% male).

RESULTS: All candidate loci were associated with metrics of epigenetic age in blood (p-adj range: .0396 to 4.5e-05) and these associations largely extended to postmortem vmPFC. There was an indirect association between PTSD severity and CLDN5 DNAm in blood at cg21872764 via GrimAge residuals (indirect β=.033, P=.040) that was diminished when the direct PTSD association was modeled. The CLDN5 probe cg17411190 in blood was negatively related to left and right hippocampal volume (p-adj=.042) and with volume of multiple hippocampal substructures. The association between PTSD severity and hippocampal volume was indirect via blood DNAm at cg17411190 (indirect β=-.011, P=.045).

CONCLUSIONS: PTSD severity-related accelerated aging may be associated with altered CLDN5 DNAm, which may signal neurodegeneration, such as reduced hippocampal volume. CLDN5 DNAm in blood may serve as a useful proxy for brain CLDN5 DNAm. Given that prior environmental enrichment and antidepressant studies show initial efficacy in altering CLDN5 expression, future studies could evaluate if PTSD treatment alters CLDN5 epigenetics and reduces risk for neurodegeneration.},
}

@article {pmid42300608,
year = {2026},
author = {Khorrami, S and Alifarsangi, A and Mohammed, LJ and Amshawee, AM and Zarrabi, A},
title = {Metal-based nanoparticles' potential in Alzheimer's disease diagnosis, therapy and theranostics.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5nr04613k},
pmid = {42300608},
issn = {2040-3372},
abstract = {Metal-based nanoparticles are emerging as a versatile platform to overcome critical challenges in the diagnosis and treatment of Alzheimer's disease (AD). This review provides a comprehensive synthesis of recent advances, structured around the three core domains of AD management: diagnostics, therapeutics, and theranostics. We discuss how the unique physicochemical properties of metals and metal oxides enable highly sensitive biosensing of amyloid and tau biomarkers, as well as high-contrast imaging modalities. The review then evaluates strategies for engineering metal-based nanoparticles to bypass the blood-brain barrier and achieve targeted accumulation, alongside their therapeutic roles in drug delivery, photothermal therapy, and modulating protein aggregation. Finally, we assess integrated theranostic systems that combine real-time imaging with targeted intervention. The key conclusion is that platforms based on metal-based nanoparticles, through their multifunctionality, offer a realistic pathway toward minimally invasive early diagnosis and targeted therapy. However, the field's future direction must prioritize rigorous standardization and advanced preclinical validation to translate these promising nanotechnologies from bench to bedside, ultimately advancing precision neurotheranostics for AD.},
}

@article {pmid42300721,
year = {2026},
author = {Song, BX and Schecter, J and Vieira, E and Gallagher, D and Diniz, BS and Fischer, CE and Flint, AJ and Herrmann, N and Kennedy, JL and Mah, L and Mulsant, B and Pollock, BG and Rajji, TK and Ma, C and Lanctôt, KL and , },
title = {Angiogenesis markers and cognitive response in a randomized trial of cognitive remediation plus transcranial direct current stimulation in older adults at risk of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261457934},
doi = {10.1177/13872877261457934},
pmid = {42300721},
issn = {1875-8908},
abstract = {BackgroundCognitive remediation (CR) combined with transcranial direct current stimulation (tDCS) has been shown to slow cognitive decline in older adults with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD). Dysregulated angiogenesis is implicated in early neurodegeneration and may influence response to these interventions.ObjectiveTo determine whether baseline plasma angiogenesis markers moderate short-term and long-term cognitive response to CR + tDCS in older adults at risk for dementia.MethodsNineteen angiogenesis-related plasma biomarkers were measured at baseline in participants from the PACt-MD randomized controlled trial. Participants received active or sham CR plus active or sham tDCS for 8 weeks, followed by semi-annual booster sessions and online CR between visits. Cognitive assessments occurred at baseline, 8 weeks, and yearly. Elastic net regression identified relevant markers and baseline variables associated with the 8-week cognitive change. For selected markers, treatment*marker interactions were tested using multivariable linear regression adjusted for relevant demographic, clinical, and genetic covariates. Significant interactions were further examined using likelihood ratio tests in linear mixed-effects models across follow-up.ResultsIn 271 participants, angiopoietin-2, endocan, and VCAM-1 were identified as relevant markers. Out of these three markers, only angiopoietin-2 interacted with treatment (β(SE) = 0.17(0.08), p = 0.04, padj = 0.11, f[2] = 0.02), with lower levels associated with greater 8-week cognitive improvement in the active treatment group, controlling for covariates. This moderating effect persisted during follow-up (χ[2]LRT(3) = 24.9, p < 0.001).ConclusionsLower baseline angiopoietin-2 may identify older adults with MCI or rMDD that are more likely to benefit from CR + tDCS.ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02386670; NCT02386670.},
}

@article {pmid42300919,
year = {2026},
author = {Peesapati, S and Chakraborty, S},
title = {Modeling the organizational heterogeneity of cholesterol-enriched microdomains in the neuronal membranes of gray and white matter of Alzheimer's brain: a computational lipidomics study.},
journal = {Soft matter},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6sm00153j},
pmid = {42300919},
issn = {1744-6848},
abstract = {Alzheimer's disease (AD) is a leading cause of death among the elderly, with no existing treatment. The development of therapies is further hindered by a limited understanding of the molecular pathogenesis and the absence of reliable early-detection biomarkers. Neuroimaging and lipidomic studies reveal structural and biochemical alterations in both gray and white matter in AD patients, including disruptions in membrane organization and neuronal signaling pathways. In the present work, we employed lipidomics-guided modeling of membranes in gray and white matter regions under healthy and diseased (AD) conditions, and used all-atom molecular dynamics (MD) simulations to examine how AD-associated alterations in lipid composition influence the structure, spatial organization, and micro-heterogeneity of neuronal plasma membranes. The data suggest that Alzheimer's disease-associated lipid alterations in gray matter (GM) and white matter (WM) impact membrane thickness and microdomain distribution, highlighting the critical role of lipid composition in maintaining neuronal membrane homeostasis and function. Higher-order cholesterol-ceramide-sphingomyelin-enriched domains are more abundant in the neuronal membranes of the GM region under diseased conditions. Under AD-mimicking conditions, lipidomic analyses demonstrate that neuronal membranes in GM experience more substantial compositional and structural remodeling than those in WM. Our results show significant changes in membrane microdomain distribution across the lipid bilayers, and, interestingly, these changes are more pronounced in the gray matter than in the white matter. This study establishes a framework for modeling the tissue-specific lipidomics data to understand how disease-driven compositional changes affect the structure, organization, and dynamics of biological membranes.},
}

@article {pmid42301522,
year = {2026},
author = {Welikovitch, LA and Oakley, DH and Bennett, RE and Serrano-Pozo, A and Zhu, H and Ruiz-Uribe, NE and Zwang, TJ and Chibnik, LB and Gomez-Isla, T and Frosch, MP and Marks, DS and Salloway, S and Bernick, C and Greeley, D and Latimer, CS and Nolan, A and Hutchison, RM and Rubel, CE and Bussiere, T and Plowey, ED and Keene, CD and Hyman, BT},
title = {Neuropathological study of the effects of aducanumab anti-Aβ immunotherapy on patients with Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42301522},
issn = {1432-0533},
support = {24AARF-1192364/ALZ/Alzheimer's Association/United States ; R01AG071567/NH/NIH HHS/United States ; UW ADRC P30 AG066509/NH/NIH HHS/United States ; P30AG062421//Massachusetts Alzheimer Disease Research Center/ ; W81XWH-21-S-TBIPH2//US Department of Defense/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/drug therapy/therapy/immunology ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; *Amyloid beta-Peptides/metabolism/immunology ; Male ; Aged ; *Brain/pathology/drug effects/metabolism ; Aged, 80 and over ; Neurofibrillary Tangles/pathology ; *Immunotherapy/methods ; Plaque, Amyloid/pathology ; tau Proteins/metabolism ; },
abstract = {Fluid and imaging biomarker data show that anti-amyloid (Aβ) antibodies promote the clearance of Aβ from the brains of patients with Alzheimer's disease (AD). We examined postmortem brain tissue of individuals who participated in aducanumab clinical trials and investigated the drug's effects on Aβ pathology and other AD phenotypes. The medial temporal lobe of six aducanumab clinical trial participants-who had extensive exposure to aducanumab and happened to die between 7 weeks and 5 years after their last antibody infusion-was compared with that of nine untreated AD patients matched for age, APOE genotype, and Braak neurofibrillary tangle stage, to determine how aducanumab impacts AD pathobiology. Patients treated with aducanumab displayed a robust reduction in Aβ burden. As observed in previous studies, Aβ was associated with non-arterial microvessels in aducanumab-treated patients, suggesting a redistribution of Aβ within the neuropil. Neuritic phospho-tau decreased in parallel with fewer Aβ plaques, but the density of PHF-1[+] and AT8[+] neurofibrillary tangles remained unchanged relative to the average untreated AD donor. Measures of microglial and astroglial reactivity were also comparable to those in untreated AD controls. These findings confirm aducanumab's potent ability to target and remove brain Aβ. On average, Aβ plaques increased in proportion to the length of time after the last dose, consistent with the idea that plaques gradually redeposit post-treatment. The selective reduction of neuritic, but not neurofibrillary tangle phospho-tau implies that Aβ-targeted antibodies such as aducanumab alleviate plaque-associated dystrophy but may not address established tangles. This study describes the long-term outcomes of anti-Aβ immunotherapy in AD.},
}

Humans
*Alzheimer Disease/pathology/drug therapy/therapy/immunology
*Antibodies, Monoclonal, Humanized/therapeutic use
Female
*Amyloid beta-Peptides/metabolism/immunology
Male
Aged
*Brain/pathology/drug effects/metabolism
Aged, 80 and over
Neurofibrillary Tangles/pathology
*Immunotherapy/methods
Plaque, Amyloid/pathology
tau Proteins/metabolism

@article {pmid42302727,
year = {2026},
author = {Kim, MS and Kang, D},
title = {Why Deep Cervical Lymphovenous Anastomosis for Alzheimer Disease Lacks Scientific Foundation.},
journal = {The Journal of craniofacial surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/SCS.0000000000013042},
pmid = {42302727},
issn = {1536-3732},
abstract = {Deep cervical lymphovenous anastomosis (DCLVA) has been rapidly adopted as a surgical treatment for Alzheimer disease (AD), based on the hypothesis that enhancing cervical lymphatic drainage may promote glymphatic clearance of neurotoxic proteins. By mid-2025, an estimated 382 hospitals in China had performed the procedure before any randomized controlled trial was completed, prompting China's National Health Commission to prohibit its clinical use on the grounds of insufficient evidence. That prohibition addressed the absence of clinical trial data but did not articulate a specific physiological objection. Following a recent critical review of lymphovenous anastomosis in the lower extremity, the senior author investigated the status of this technique in the craniofacial region and found that its dominant application is not for head and neck lymphedema but for AD. This review identifies fundamental scientific gaps in the rationale for DCLVA in AD. The target pathology-cervical lymphatic insufficiency-has never been confirmed in living patients with AD. Preclinical evidence is contradictory: modulating dural lymphatic vessels in either direction does not alter amyloid pathology in mouse models. No study has controlled for confounding anesthetic effects. No standardized surgical protocol exists. Hemodynamic conditions at the anastomotic site during supine sleep-when glymphatic clearance is most active-have never been measured. Serious adverse events have already been reported. These gaps represent deficiencies in the fundamental science that must be resolved before clinical investigation can be justified.},
}

@article {pmid42304162,
year = {2026},
author = {Madhu, LN and Attaluri, S and Kotian, S and Upadhya, R and Somayaji, Y and Rao, S and Tarale, P and Ganesh, SV and Huard, C and Kodali, M and Shuai, B and Rao, VV and Shetty, AK},
title = {Human iPSC-NSC-Derived Extracellular Vesicles Can Alleviate Alzheimer's Disease-Linked Impairments in Mitochondria, mTOR Signaling, Autophagy, and Hippocampal Neurogenesis.},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70590},
pmid = {42304162},
issn = {1474-9726},
support = {RF1AG074256/AG/NIA NIH HHS/United States ; R01AG075440/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *TOR Serine-Threonine Kinases/metabolism ; Humans ; Animals ; *Mitochondria/metabolism ; *Hippocampus/metabolism/pathology ; *Neurogenesis ; Mice ; Signal Transduction ; *Induced Pluripotent Stem Cells/metabolism ; *Autophagy ; Male ; *Extracellular Vesicles/metabolism/transplantation ; *Neural Stem Cells/metabolism ; Female ; },
abstract = {Intranasal (IN) administrations of extracellular vesicles (EVs) derived from human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSCs) have shown promise in reducing chronic neuroinflammation mediated by microglia and astrocytes in 5x familial Alzheimer's disease (5xFAD) mice, a model for early-onset Alzheimer's disease (AD). The current study rigorously investigated whether treatment with hiPSC-NSC-EVs could also alleviate several other neuropathological changes contributing to progressive cognitive decline. Three-month-old male and female 5xFAD mice received IN administrations of either hiPSC-NSC-EVs (~30 × 10[9]/week for 2 weeks) or vehicle. Two months later, the hippocampus of both male and female 5xFAD mice treated with the vehicle showed increased levels of markers of oxidative stress and mechanistic target of rapamycin (mTOR) signaling, altered expression of genes and/or proteins linked to mitochondria and autophagy, and diminished neurogenesis. In contrast, treatment with hiPSC-NSC-EVs restored levels of oxidative stress markers and the expression of genes and/or proteins linked to various mitochondrial complexes, mitochondrial biogenesis, fission, fusion, and mitophagy closer to naïve control levels, indicating alleviation of mitochondrial impairments. These improvements were accompanied by reduced phosphorylated mTOR levels and multiple autophagy markers matching those in naïve controls, suggesting a dampening of mTOR signaling and an enhancement of autophagy. Furthermore, mice treated with hiPSC-NSC-EVs showed increased hippocampal neurogenesis, associated with enhanced brain-derived neurotrophic factor signaling. Overall, the results highlight that IN administrations of hiPSC-NSC-EVs in the early stages of AD can help slow the progression of multiple neuropathological changes associated with cognitive decline in 5xFAD mice and potentially AD.},
}

*Alzheimer Disease/metabolism/pathology
*TOR Serine-Threonine Kinases/metabolism
Humans
Animals
*Mitochondria/metabolism
*Hippocampus/metabolism/pathology
*Neurogenesis
Mice
Signal Transduction
*Induced Pluripotent Stem Cells/metabolism
*Autophagy
Male
*Extracellular Vesicles/metabolism/transplantation
*Neural Stem Cells/metabolism
Female

@article {pmid42304897,
year = {2026},
author = {Kim, S and Park, SK},
title = {Fucoxanthin Promotes Longevity and Neuroprotection in Caenorhabditis elegans via DAF-16 and Autophagy Pathways.},
journal = {Rejuvenation research},
volume = {},
number = {},
pages = {15491684261460844},
doi = {10.1177/15491684261460844},
pmid = {42304897},
issn = {1557-8577},
abstract = {Identification of natural compounds that delay aging and prevent age-related neurodegeneration is a key goal in gerontology. Fucoxanthin, a marine-derived xanthophyll, exhibits potent antioxidant properties, yet its effects on organismal aging and specific molecular mechanisms remain underexplored. Here, we investigated the pro-longevity and neuroprotective effects of fucoxanthin using Caenorhabditis elegans. Fucoxanthin supplementation significantly extended the mean lifespan of wild-type nematodes by 12.1% and improved health span, as evidenced by delayed age-related motility decline and enhanced resistance to oxidative stress. Notably, this lifespan extension occurred without compromising reproductive fitness. Genetic analysis revealed that the beneficial effects of fucoxanthin require the FOXO transcription factor DAF-16 and the autophagy-essential gene bec-1. Furthermore, fucoxanthin treatment increased autophagic flux and upregulated the expression of SKN-1/Nrf2-dependent detoxification genes, hsp-16.2 and gst-4. In nematode models of Alzheimer's and Parkinson's disease, fucoxanthin significantly ameliorated Aβ-induced paralysis and protected against dopaminergic neurodegeneration and α-synuclein accumulation in a DAF-16-dependent manner. Collectively, our findings demonstrate that fucoxanthin acts as a multitarget geroprotector that promotes healthy aging through the coordinated activation of DAF-16 and autophagy, suggesting its potential as a therapeutic intervention for age-related decline.},
}

@article {pmid42304917,
year = {2026},
author = {Sinha, S and Gupta, S and Tiwari, P},
title = {Therapeutic Potential of Natural Chalcones Against Alzheimer's Disease: A Mechanistic Insight.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454130260605061515},
pmid = {42304917},
issn = {1875-5739},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, amyloid-beta (Aβ) plaque deposition, tau hyperphosphorylation, oxidative stress, and chronic neuroinflammation. Therapeutic strategies are at present mainly symptomatic and do not modify the course of the disorder. Natural chalcones, precursors of flavonoids, are emerging as multi-target agents for neuroprotection since they have the ability to protect neurons and exert anti-inflammatory and antioxidant activities.

METHODS: A systematic literature search was performed in PubMed, Scopus, Web of Science, and Google Scholar utilizing keywords that associate chalcones with Alzheimer's disease. Studies were included if they reported in silico docking, in vitro assays, or mechanistic insights on AD-related targets (AChE, BACE1, GSK-3β, NF-κB). Data extraction included information about the compound's identity, structural changes, docking scores, enzyme inhibition, oxidative stress, and cytokine modulation. The findings were synthesized both qualitatively and quantitatively, with structure-activity relationship (SAR) analysis emphasizing patterns of hydroxylation and methoxylation. These helped in the rational design of chalcone derivatives, which showed potential as multi-target agents against AD pathology.

RESULTS: Several chalcones exhibited potent inhibition against AChE and BACE1, besides reducing reactive oxygen species (ROS) generation and preventing the release of pro-inflammatory cytokines. These findings demonstrate their potential to mitigate cholinergic deficits and neuroinflammatory signaling. SAR studies revealed a significant enhancement in bioactivity for certain hydroxylation and methoxylation substituents. This provides insights into the rational design of improved chalcone derivatives.

DISCUSSION: Chalcones display multifunctional properties and are able to modulate several AD pathological signatures, suggesting potential application in the prevention of AD symptoms. Their therapeutic importance is emphasized by their combined ability to target cholinergic dysfunction, oxidative stress, and neuroinflammation. The SAR analysis further supports the focused development of chalcone-based derivatives with improved potency.

CONCLUSION: The present study provides insights into the mechanistic basis of the neuroprotective activity of chalcones and paves the way for subsequent preclinical evaluation. The chalconebased strategy holds promise for the development of potential drug candidates for the treatment of neurodegenerative diseases such as Alzheimer's disease by addressing the multi-target nature of this complex disease.},
}

@article {pmid42305190,
year = {2026},
author = {Sedlacek Miskerikova, M and Houfkova, A and Benkova, M and Andrys, R and Janousek, J and Soukup, O and Musilek, K and Benek, O},
title = {Development of Novel 17β-HSD10 Inhibitors and Their Evaluation in an In Vitro Model of Alzheimer's Disease.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {6},
pages = {1347-1354},
pmid = {42305190},
issn = {1948-5875},
abstract = {17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a multifunctional mitochondrial enzyme and a potential drug target for the treatment of various pathologies, including Alzheimer's disease (AD). In this study, five new benzothiazole-derived 17β-HSD10 inhibitors were developed based on structure-activity relationship (SAR) analyses of previously published compounds. To evaluate the inhibitory effects, cytotoxicity, and therapeutic potential of these new compounds, several enzyme- and cell-based methods were employed. All prepared compounds exhibited high inhibitory potential and confirmed good biomembrane permeation. Three inhibitors (9b, 9c, and 15a) showed lower IC50 values in both enzyme- and cell-based assays than the formerly published hit compounds. The compounds were also found to reduce the pathological effects associated with 17β-HSD10 overexpression, although not the combined pathological effects of 17β-HSD10 overexpression within an amyloid-β rich environment.},
}

@article {pmid42305665,
year = {2026},
author = {Vignesh Pandi, A and Malakar, V and Jeyabalan, JB and Sanjai, M and Shevate, K and Rajagopal, K and Prashantha Kumar, BR and Justin, A},
title = {Integrated computational-based design of putative dual TrkA/TrkB agonists for Alzheimer's disease: pharmacophore modelling, docking, MM/GBSA, DFT and dynamics studies.},
journal = {Frontiers in bioinformatics},
volume = {6},
number = {},
pages = {1779769},
pmid = {42305665},
issn = {2673-7647},
abstract = {BACKGROUND: The rapid progression of Alzheimer's disease (AD) is primarily caused by compromised neurotrophin functions and decreased tropomyosin receptor kinase expression in the basal forebrain area. The two main pathogenic features of AD are cholinergic-dependent cognitive dysfunctions and amyloidogenic-induced neurodegeneration. Concurrent stimulation of major neurotrophin signalling pathways, such as tropomyosin receptor kinases receptor A and B (TrkA and TrkB), may reduce amyloid-β-mediated neurotoxicity and cholinergic denervation in the basal forebrain, improving cognitive performance and re-establishing neuronal communication. The development of new medications with dual agonist action towards TrkA and B receptors holds enormous therapeutic potential for managing the symptoms of neurodegenerative diseases.

AIM: This study aims to develop novel dual TrkA/TrkB receptor agonists for the treatment of AD by enhancing neurotrophin signalling, reducing cholinergic denervation, and mitigating amyloid-β-induced neurotoxicity.

METHODS: An in silico drug discovery pipeline was employed, involving homology and pharmacophore modelling of amitriptyline, virtual screening of ChEMBL compounds, molecular docking, ADMET, MM/GBSA analysis, DFT calculations and molecular dynamics (MD) simulations for 100 and 300 ns to assess ligand stability and binding behaviour of the ligand-protein complexes.

RESULTS: Six novel optimised quinoline analogues (OP-1 to OP-6) were identified as computationally predicted dual TrkA/TrkB agonists by molecular docking (-8.90 to -5.07 kcal/mol), MM/GBSA (-40.47 to -30.71 kcal/mol), ADMET and DFT analysis. Furthermore, OP-1, OP-2, and OP-3 exhibit stable binding interactions over 300 ns of MD simulations. The optimised compounds demonstrated favorable computational binding profiles, predicted pharmacokinetic properties, and stable receptor-ligand interactions, identifying them as promising candidates for further experimental validation as potential dual TrkA/TrkB modulators in Alzheimer's disease.},
}

@article {pmid42306035,
year = {2026},
author = {Kalpaktsi, I and Panara, A and Mavroidi, B and Niforos, GG and Kalampaliki, AD and Vlachogianni, IC and Georgiou, EA and Fragopoulou, E and Tsarbopoulos, A and Skaltsounis, AL and Pelecanou, M and Palikaras, K and Gikas, E and Kostakis, IK},
title = {Novel hydroxytyrosol esters as potential anti-amyloid and neuroprotective agents for Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42306035},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is associated with the aggregation of β-amyloid (Aβ) peptides and oxidative stress, two interconnected processes that contribute to neuronal dysfunction and cognitive decline. Natural polyphenols such as oleuropein and its metabolite hydroxytyrosol display antioxidant and anti-amyloidogenic properties, but oleuropein suffers from limited stability due to glycosidic hydrolysis. To develop more robust and potent oleuropein analogs, we synthesized a series of hydroxytyrosol-based esters in which the secoiridoid glucoside scaffold of oleuropein was replaced by lipophilic substituents designed to enhance molecular stability and interactions with Aβ peptide. The compounds were evaluated for their ability to interact with Aβ40 using ESI-MS, circular dichroism (CD), and thioflavin-T fluorescence (ThT), along with complementary antioxidant assays. Most of the compounds formed stable non-covalent complexes with Aβ40, inhibited early aggregation events, and prevented the peptide's conformational transition from random coil to β-sheet. To assess biological efficacy and safety in vivo, the most promising analog (3b) was evaluated in Caenorhabditis elegans models of amyloid-β toxicity. Treatment with 3b exhibited no detectable toxicity in wild-type animals, as evidenced by normal development, growth, and reproductive efficacy. Importantly, 3b rescued lifespan shortening and locomotor deficits in transgenic nematodes expressing human Aβ42 pan-neuronally, while having no effect on control strains lacking Aβ42 expression. These findings demonstrate that 3b confers functional protection against amyloid-induced toxicity in vivo. Overall, our results identify the newly synthesized hydroxytyrosol-derived esters as promising multifunctional scaffolds that combine potent anti-aggregation activity with strong antioxidant properties and in vivo neuroprotective efficacy, supporting their further development as anti-amyloidogenic agents for AD therapy.},
}

@article {pmid42306774,
year = {2026},
author = {Rodriguez Martinez, PJ and Yslas, AR and Inoue, Y and Parsons, TM and Baker, SK and Lu, W and Raulin, AC and Kanekiyo, T},
title = {APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.},
journal = {Frontiers in molecular biosciences},
volume = {13},
number = {},
pages = {1778856},
pmid = {42306774},
issn = {2296-889X},
abstract = {Aging and neurodegenerative disorders like Alzheimer's Disease (AD) are associated with progressive dysfunction of the blood-brain barrier (BBB) and neurovascular unit (NVU), contributing to impaired vascular integrity and neuronal vulnerability. Apolipoprotein E (APOE) is a key regulator of neurovascular function, and the rare APOE3-R136S "Christchurch" variant (APOE3Ch) confers protection against AD. Mesenchymal stromal cells (MSCs) represent a promising cell-based therapy for the treatment of neurodegenerative diseases due to their paracrine effect exerted on vascular and neural cells. To investigate how APOE3Ch influences MSC-mediated neurovascular support, we used isogenic iPSC-derived MSCs (iMSCs) with homozygous APOE3Ch or APOE3. We found that APOE3Ch iMSCs have stronger immunosuppressive effect on LPS-induced NFκB activation of THP1 cells. APOE3Ch iMSCs also enhanced endothelial barrier resistance and angiogenic capacity compared to APOE3 iMSCs when directly co-cultured with endothelial cells. In addition, conditioned medium from APOE3Ch iMSCs promoted neurite outgrowth more efficiently than that from APOE3 iMSCs. Metabolic profiling revealed differences between APOE3Ch and APOE3 iMSCs, suggesting altered metabolic resilience. Together, these findings demonstrate that iMSCs support vascular and neuronal function through paracrine mechanisms and suggest that APOE3Ch variant improves specific aspects of MSC-mediated neurovascular support. This work highlights the potential of combining MSC-based therapies with protective APOE variants to target BBB and NVU dysfunction in aging and neurodegeneration.},
}

@article {pmid42293147,
year = {2026},
author = {Pinky, and Neha, and Kaushik, M and Tiwari, P and El-Tanani, M and Rabbani, SA and Parvez, S},
title = {Propranolol reinstates mitochondrial dynamics and synaptic memory pathways through CaMKII/CREB-BDNF/ PKMζ cascades in an AD-like rat model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729046},
pmid = {42293147},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, neurofibrillary tangles, and progressive cognitive decline. Despite significant advances in understanding its pathophysiology, current therapeutic options provide limited symptomatic relief. The present study investigated the nootropic and anti-amnesic effects of propranolol (PRO) in a scopolamine (SCP)-induced AD-like rat model.

METHODS: Wistar rats received PRO (10, 30, or 50 mg/kg, p.o.) or donepezil (DPZ; 1 mg/kg) for 17 days. Cognitive deficits were induced by SCP (1 mg/kg, i.p.) administration from day 9 onward. Behavioral performance was assessed using the Novel Object Recognition (NOR) and Elevated Plus Maze (EPM) tests. Molecular and cellular analyses were conducted to evaluate synaptic plasticity markers (CaMKII, CREB, BDNF, PKMζ), mitochondrial function, oxidative stress parameters, and inflammatory markers (GFAP, TNF-α).

RESULTS: Propranolol treatment significantly improved long-term memory performance, enhanced recognition index, and attenuated anxiety-like behavior in SCP-treated rats. These behavioral effects were associated with upregulation of CaMKII-CREB-BDNF-PKMζ signaling, improvement in mitochondrial membrane potential (Δψm), reduction in reactive oxygen species (ROS) generation and Aβ1-42 accumulation, and decreased expression of GFAP and TNF-α.

CONCLUSION: The findings suggest that propranolol mitigates SCP-induced cognitive impairments, potentially through modulation of synaptic plasticity- related signaling, mitochondrial function, and neuroinflammatory responses. These results indicate the therapeutic potential of propranolol in experimental models of AD-related neurodegeneration, warranting further investigation.},
}

@article {pmid42294918,
year = {2026},
author = {Singh, M and Steinke, I and Crall, N and Tamhankar, S and Wibowo, FS and Xavier, J and Yue, Z and Pondugula, SR and Huang, CJ and Griffett, K and Smith, FT and Chowdhury, K and Suppiramaniam, V and Amin, RH},
title = {Design and Development of a Novel LXRβ/PPARδ Dual Agonist for Memory Impairment and Pathology in 3xTg-AD Animal Model of Alzheimer's Disease.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.6c00240},
pmid = {42294918},
issn = {1554-8937},
abstract = {The rising prevalence of Alzheimer's disease (AD) underscores an urgent need for neuroprotective strategies that modulate cholesterol metabolism, neuroinflammation, improve pathology, and cognitive function. While Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are validated targets for enhancing amyloid-β and tau clearance, clinical translation of first-generation LXR agonists has been hindered by LXRα-mediated hepatic steatosis and hypertriglyceridemia. Here, we report the structure-based design of AU403, a potent, isoform-selective LXRβ/PPARδ dual agonist designed to bypass LXRα-driven hepatotoxicity. Molecular modeling indicates that AU403 achieves LXRβ selectivity by engaging residues Phe329 and Leu330 while avoiding the corresponding LXRα residues Arg305 and Leu316. This structural precision translates to robust functional activity, with luciferase assays confirming potent activation of LXRβ (EC50 ≈ 45 nM) and PPARδ (EC50 ≈ 40 nM). Notably, AU403 exhibits a superior safety profile, circumventing hepatotoxicity, neutropenia, and hERG inhibition that have limited the clinical development of prior agonists. Furthermore, chronic administration of AU403 in 3xTg-AD mice significantly improved cognitive functions and reduced amyloid-β plaque burden, establishing AU403 as a promising dual-acting agonist for the treatment of Alzheimer's Disease.},
}

@article {pmid42295086,
year = {2026},
author = {Liu, Q and Lin, RR},
title = {Optimizing Antibody-Based Therapies for Alzheimer's Disease: From Clinical Limitations to Molecular Engineering Innovations.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0292},
pmid = {42295086},
issn = {2152-5250},
abstract = {Antibody-based immunotherapy represents one of the most promising disease-modifying strategies for Alzheimer's disease (AD). Recent anti-amyloid-β (Aβ) antibodies have achieved robust plaque clearance and modest cognitive benefits in early AD, establishing clinical proof of concept. However, limited efficacy and safety concerns, particularly amyloid-related imaging abnormalities (ARIA), continue to restrict their therapeutic potential. This review outlines the current clinical status of antibody therapies targeting Aβ, tau, and neuroinflammatory pathways, and summarizes key antibody optimization strategies, including aggregation-state-selective targeting, Fc engineering, brain shuttle technologies, nanobody platforms, and nanotechnology-enabled delivery. We further discuss emerging concepts from tumor immunotherapy, such as antibody-guided protein degradation and conditionally active biologics, as potential avenues for next-generation AD treatment.},
}

@article {pmid42295611,
year = {2026},
author = {Guo, Y and Chen, P and Chen, S and Xu, N and Shi, J and Li, D and Zhang, P},
title = {Circ_0092222 is Enhanced in Alzheimer's Disease and Exacerbates Aβ-induced Neurotoxicity Through Sponging miR-331-3p.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42295611},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/blood/metabolism ; *Amyloid beta-Peptides/toxicity ; *MicroRNAs/genetics/metabolism ; *RNA, Circular/genetics/metabolism ; Cell Line, Tumor ; Apoptosis/drug effects/genetics ; Female ; Male ; Cell Survival/drug effects ; Neurons/metabolism/drug effects/pathology ; *Peptide Fragments/toxicity ; RNA, Competitive Endogenous ; },
abstract = {This study aimed to explore the expression pattern of circ_0092222 in Alzheimer's disease (AD) and its role in Aβ-induced neuronal apoptosis. circ_0092222 was identified from the GEO dataset. Serum level of circ_0092222 in 95 AD patients and 100 controls was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). AD cell model was achieved by treating SH-SY5Y cells with Aβ25-35. Cell viability, cytotoxicity, apoptosis and inflammation were detected. The targeting relationship between circ_0092222 and miR-331-3p, and between miR-331-3p and SEC61A1 was verified by the dual-luciferase reporter gene assay. Pearson correlation and Logistic regression analysis were used to evaluate the relationship between variables and the risk factors for AD progression. Circ_0092222 expressions in AD patients were higher than that in the control group. Short years of education, low mini mental state examination (MMSE) score, low plasma Aβ42/40 ratio, and elevated circ_0092222 were independent risk factors for the progression of mild AD to moderate/severe. In cell experiments, the expression of circ_0092222 was upregulated. Knockdown of circ_0092222 could significantly reduce the apoptosis rate, lactate dehydrogenase (LDH) release, pro-inflammatory cytokine levels, and the expressions of Bax and cleaved caspase-3, and increase cell viability and Bcl-2 expression. Bioinformatics prediction and dual-luciferase reporter gene assay confirmed that circ_0092222 directly binds to miR-331-3p, and miR-331-3p directly targets SEC61A1. Functional rescue experiments demonstrated that circ_0092222 regulates Aβ25-35-induced neuronal injury by up-regulating SEC61A1 through sponging miR-331-3p. Inhibiting circ_0092222 can improve Aβ25-35-induced apoptosis and inflammation, suggesting that circ_0092222 may be a potential target for AD treatment.},
}

Humans
*Alzheimer Disease/genetics/pathology/blood/metabolism
*Amyloid beta-Peptides/toxicity
*MicroRNAs/genetics/metabolism
*RNA, Circular/genetics/metabolism
Cell Line, Tumor
Apoptosis/drug effects/genetics
Female
Male
Cell Survival/drug effects
Neurons/metabolism/drug effects/pathology
*Peptide Fragments/toxicity
RNA, Competitive Endogenous

@article {pmid42295692,
year = {2026},
author = {Nath, R and Chakraborty, A and Akhtar, MJ and Maity, I and Ganguly, S and Nehra, B and Ashique, S and Khan, SA and Tariq, M and Bakshi, S and Debnath, B and Yasmin, S and Khalilullah, H and Ansari, MY},
title = {Recent trends in anti-Alzheimer's potential of novel biologically active isatin analogues: synthetic strategies, structural activity relationship studies and molecular docking insights.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42295692},
issn = {1573-501X},
abstract = {Alzheimer's disease is a progressive neurodegenerative illness i.e., characterized by cognitive decline, memory impairment, cholinergic dysfunction, oxidative stress, Aβ aggregation, tau hyperphosphorylation and neuroinflammation. Due to multifactorial nature of AD, conventional single-target therapeutic approaches exhibit limited clinical success. Hence, development of multifunctional small molecules emerged as a promising strategy for management of Alzheimer's diseases i.e., capable to modulate multiple pathological pathways simultaneously. Among various heterocyclic pharmacophores, isatin (1H-indole-2,3-dione) gained considerable attention due to its structural versatility, synthetic accessibility and broad spectrum of biological effects. Recent studies demonstrated that isatin-derived molecules possess significant inhibitory activity against acetylcholinesterase, butyrylcholinesterase, monoamine oxidase-A/B, β-secretase and amyloid aggregation pathways. Furthermore, hybridization of isatin core with pharmacologically active moieties like triazoles, coumarins, tacrine, benzylamine, piperazine, quinoline, hydrazones and melatonin afford more promising multitarget-directed ligands with improved BBB permeability, antioxidant potential and improved neuroprotective properties. Also, docking, MD simulation and ADMET analyses validated favorable binding interactions and drug-likeness characteristics of many isatin analogues. This review comprehensively summarizes recent advances in design, synthesis, biological evaluation, docking investigations and SAR studies of isatin-based anti-Alzheimer agents. In addition, key emphasis is placed on SAR trends which is responsible for promoted potency and selectivity including electron-withdrawing substitutions, linker optimization, hydrophobic interactions and dual-site binding with catalytic as well as peripheral anionic sites of target enzymes. Integration of hybrid isatin scaffolds with complementary pharmacophore combined with advanced in silico modeling and preclinical evaluation may pave the way for next-generation multifunctional therapeutics with improved efficacy and safety in treatment of Alzheimer's disease.},
}

@article {pmid42297456,
year = {2026},
author = {Alghamdi, A and Balafas, S and Bos, JHJ and van Munster, BC and Rafie, K and Dolga, AM and Hak, E},
title = {Association between the use of anti-herpetic drugs and subsequent initiation of Alzheimer's disease drug treatment: Dutch population-based inception cohort study.},
journal = {BMJ open},
volume = {16},
number = {6},
pages = {e114033},
doi = {10.1136/bmjopen-2025-114033},
pmid = {42297456},
issn = {2044-6055},
mesh = {Humans ; Female ; Aged ; *Alzheimer Disease/drug therapy/epidemiology ; Netherlands/epidemiology ; *Antiviral Agents/therapeutic use ; Retrospective Studies ; Male ; Middle Aged ; Aged, 80 and over ; Valacyclovir/therapeutic use ; Acyclovir/therapeutic use ; Famciclovir/therapeutic use ; Proportional Hazards Models ; Memantine/therapeutic use ; Donepezil/therapeutic use ; },
abstract = {OBJECTIVES: To examine whether exposure to anti-herpetic drugs (AHDs: acyclovir, valacyclovir, famciclovir) is associated with reduced risk of Alzheimer's disease (AD) treatment initiation.

DESIGN: Population-based retrospective matched cohort study.

SETTING: University Groningen community pharmacy database IADB.nl, covering approximately 125 Dutch pharmacies (1994-2024).

PARTICIPANTS: 262 757 adults aged 50-80 years without prior dementia or AD treatment. Exposed individuals with antiherpetic prescriptions (n=23 887) were matched 1:10 to unexposed controls (n=238 870) by age, sex and calendar time.

INTERVENTION: AHDs: acyclovir, valacyclovir, famciclovir.

MAIN OUTCOME MEASURES: Initiation of AD drug treatment, defined as at least two prescriptions for rivastigmine, donepezil, galantamine or memantine within 1 year. Cox proportional hazards models estimated HRs with 95% CIs, adjusted for comorbidities and medications. Analyses were stratified by period (1994-2018 vs 2019-2024) and drug type.

RESULTS: During follow-up, 2495 participants initiated AD treatment. The age of the participants was 65 (SD 9), and 59% were female. Any AHD exposure was associated with 90% reduced hazard of AD treatment (HR 0.09, 95% CI 0.07 to 0.13, p<0.001). Similar association was found in both periods: HR 0.14 (95% CI 0.09 to 0.20) in period one and HR 0.05 (95% CI 0.03 to 0.10) in period 2. All three AHDs were associated with a lower likelihood of future AD drug prescription: valacyclovir HR 0.10, acyclovir HR 0.09, famciclovir HR 0.07. The incidence rate of AD treatment initiation was substantially lower among AHD users compared with unexposed individuals overall (0.69/1000 person-years (py) vs 4.96/1000 py, p<0.001), with this association evident in both period 1 (0.65/1000 py vs 3.74/1000 py, p<0.001) and period 2 (0.81/1000 py vs 8.22/1000 py, p<0.001).

CONCLUSIONS: AHD exposure was consistently associated with markedly lower risk of AD treatment initiation, with similar findings observed in recent years. These findings support the hypothesis that herpesvirus reactivation may contribute to AD pathogenesis and suggest antiviral therapy could have preventive implications. Confirmation through prospective studies and randomised trials is needed.},
}

Humans
Female
Aged
*Alzheimer Disease/drug therapy/epidemiology
Netherlands/epidemiology
*Antiviral Agents/therapeutic use
Retrospective Studies
Male
Middle Aged
Aged, 80 and over
Valacyclovir/therapeutic use
Acyclovir/therapeutic use
Famciclovir/therapeutic use
Proportional Hazards Models
Memantine/therapeutic use
Donepezil/therapeutic use

@article {pmid42298279,
year = {2026},
author = {Siengsukon, CF and Hand, LK and Nelson, E and Glaser, A and Ludwig, R and Russell, JA and Phadnis, MA and Dai, J and Bruce, J and Vidoni, ED and Drerup, M and Morris, J and Burns, JM},
title = {The impact of cognitive behavioral therapy for insomnia on cognitive performance and amyloid beta in older adults: A randomized controlled trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71591},
pmid = {42298279},
issn = {1552-5279},
support = {R01AG058530/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; T32 AG078114/AG/NIA NIH HHS/United States ; T32HL007028/NH/NIH HHS/United States ; T32HD057850//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; *Amyloid beta-Peptides/metabolism ; Female ; *Sleep Initiation and Maintenance Disorders/therapy/psychology/metabolism ; Aged ; Male ; *Cognition/physiology ; Neuropsychological Tests ; Alzheimer Disease ; Aged, 80 and over ; Executive Function ; },
abstract = {INTRODUCTION: Insomnia is associated with increased risk for Alzheimer's disease (AD). It is unknown how cognitive behavioral therapy for insomnia (CBT-I) impacts two hallmarks of AD progression, cognitive performance and beta-amyloid (Aβ) burden.

METHODS: Cognitively normal older adults with symptoms of insomnia were randomized into CBT-I treatment (n = 100) or control (n = 100) groups. Cognitive performance was assessed at baseline, 6-weeks, and 1-year (1 year). Aβ burden was assessed in a subsample (n = 50).

RESULTS: No differences were observed between groups in change in cognitive performance, including speed of information processing (mean difference, 0.017; 95% confidence interval [CI], -0.1036 to 0.1376; p = 0.78), executive function (-0.0881; 95% CI, -0.2945 to 0.1182; p = 0.40), and memory (0.4068; 95% CI, -2.3965 to 3.2101; p = 0.77). No group differences were observed in Aβ deposition.

DISCUSSION: CBT-I did not improve cognitive performance or Aβ deposition by one year. Longer follow up is needed to understand the potential impact of CBT-I on AD risk.

CLINICAL TRIAL REGISTRATION: The study was registered on clinicaltrials.gov (NCT03954210) on 5/17/2019.},
}

Humans
*Cognitive Behavioral Therapy/methods
*Amyloid beta-Peptides/metabolism
Female
*Sleep Initiation and Maintenance Disorders/therapy/psychology/metabolism
Aged
Male
*Cognition/physiology
Neuropsychological Tests
Alzheimer Disease
Aged, 80 and over
Executive Function

@article {pmid42298289,
year = {2026},
author = {Amouyel, P and Andrieu, S and Bradshaw, A and Carmona, RC and Dumont, M and Grinberg, LT and Iwatsubo, T and Hansson, O and Jack, CR and Jicha, GA and Mahinrad, S and McDade, E and Mummery, CJ and Petersen, RC and Robinson, S and Schneider, JA and Shellcross, L and Smith, AG and Snyder, HM and Tapply, B and Teunissen, C and van der Flier, WM and Vellas, B and Wallon, D and Williamson, JD and Wilcock, D and Carrillo, MC},
title = {Provider and patient perspectives on the diagnosis and treatment of Alzheimer's disease: A global perspective from the Global Alzheimer's Leadership Series (GoALS).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {6},
pages = {e71536},
pmid = {42298289},
issn = {1552-5279},
mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; },
abstract = {Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world-leading experts for innovative discussions to advance Alzheimer's disease (AD) research and care. The second GoALS think tank, held in June 2024 in Paris, focused on the relationship between biological changes and clinical manifestations of AD in the context of the evolving therapeutic landscape. Discussions spanned real-world experiences of providers, patients, and their families, theoretical considerations, and health system challenges. The lived experience perspective was central to these discussions. The importance of shared decision-making, clear and transparent communication, and the need for real-world data to holistically support patients during their experiences were highlighted. This manuscript shares key insights from both the think tank meeting in Paris and a featured research session at the 2024 Alzheimer's Association International Conference that expanded the discussion themes for broader dissemination with the community.},
}

*Alzheimer Disease/diagnosis/therapy
Humans

@article {pmid42298621,
year = {2026},
author = {Gezginer, I and Karakatsani, ME and Nanda, P and Chalasani, P and Kindler, D and Storz, R and Belau, M and Ni, R and Schratt, G and Deán-Ben, XL and Razansky, D},
title = {Transcranial pulse stimulation modulates spectral signatures of Alzheimer's disease in the 3×Tg-AD mouse model.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02109-1},
pmid = {42298621},
issn = {1758-9193},
abstract = {BACKGROUND: Large-scale brain network dysfunction is increasingly recognized as an important feature of Alzheimer's disease (AD), offering insight into disease mechanisms and opportunities for targeted therapeutic intervention. The spectral features of this dysfunction remain poorly understood, and how neuromodulatory interventions interact with and reshape these frequency-resolved network signatures has yet to be explored.

METHODS: Triple-transgenic (3×Tg-AD) mice underwent resting-state functional MRI to assess functional connectivity, signal power, and variance across frequency bands after acute and longitudinal transcranial pulse stimulation (TPS), a low-intensity single-pulse neuromodulatory intervention. Novel object recognition testing was used to evaluate exploratory drive and short-term recognition memory following repeated TPS or sham treatment.

RESULTS: AD mice exhibited widespread functional connectivity loss accompanied by reduced low-frequency resting-state power and variance, together with a redistribution of spectral energy from slow-5 (0.01-0.027 Hz) to slow-4 (0.027-0.073 Hz) activity. TPS modulated these abnormalities by increasing low-frequency power, rebalancing slow-5/slow-4 fractional power, and strengthening network coherence, with the most prominent effects in cingulate, insular, piriform, and striatal regions. TPS effects showed a non-linear, region-dependent emergence across stimulation trains, with the strongest and most consistent modulation appearing after repeated stimulation. Similar spectral rebalancing was observed both after acute and longitudinal stimulation, persisting for up to 5 days. In addition, hippocampal regions that showed minimal acute responses exhibited delayed spectral changes at 24 h, with further modulation at 120 h. TPS-treated 3×Tg-AD mice did not show the decline in object exploration observed in sham-treated animals and showed an exploration-adjusted increase in novel object preference.

CONCLUSIONS: Frequency-specific neural dynamics are sensitive markers of AD-related dysfunction and may provide a useful framework for tracking disease-related network abnormalities. TPS selectively modulates low-frequency oscillatory activity and network coherence and is accompanied by preliminary behavioral changes, including preserved exploratory engagement and an exploration-adjusted increase in novel object preference in a separate behavioral cohort. This highlights the potential of combining neuromodulation with spectral network analysis to monitor disease-related network dysfunction and treatment-associated responses.},
}

@article {pmid42299007,
year = {2026},
author = {Imai, N and Yano, H and Ikegame, Y and Yasuda, S and Morishima, R and Okumura, A and Kumagai, M and Shinoda, J and Izumo, T},
title = {Cerebral Hyperperfusion with Lecanemab in Alzheimer's Disease Assessed by Amyloid PET and Arterial Spin Labeling.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050453079260226065149},
pmid = {42299007},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Alzheimer's Disease (AD) is characterized by cognitive decline, amyloid-β deposition, and decreased Cerebral Blood Flow (CBF). Lecanemab, a monoclonal antibody targeting amyloid-β, slows cognitive decline in AD; however, its effects on CBF remain unclear. This study aimed to characterize CBF changes following lecanemab treatment and their association with baseline amyloid burden.

METHODS: Thirty patients with AD treated with lecanemab were analyzed retrospectively. Baseline amyloid deposition was quantified using the Centiloid scale, and patients were stratified into low, middle, and high groups. CBF was analyzed at baseline and at 8, 12, and 26 weeks using arterial spin labeling (ASL). Monoclonal antibody-triggered cerebral hyperperfusion (MATCH) was defined as a >20% CBF increase at week 8.

RESULTS: Seven patients were MATCH-positive (median CBF: 133.5% [125.5-167.8] of baseline). All MATCH-positive patients exhibited a decrease in CBF at week 12 compared to week 8. MATCH occurred in 6 of 10 patients in the middle Centiloid group. The low Centiloid group showed stable CBF, while the high Centiloid group showed a decreasing trend. The MATCHpositive group showed a significant deterioration in Instrumental Activities of Daily Living scores.

DISCUSSION: A transient CBF increase was closely associated with the middle Centiloid group. These CBF responses, including MATCH, may reflect amyloid removal, hyperperfusion, amyloidrelated imaging abnormalities, or immune responses.

CONCLUSIONS: CBF changes differed according to baseline amyloid burden. Understanding these therapy-related CBF changes is crucial for elucidating AD pathology, and ASL provides a practical, non-invasive method for longitudinal CBF monitoring in routine clinical practice.},
}

@article {pmid42299502,
year = {2026},
author = {Liu, M and Hong, H and Zhang, X and Ren, J and Tang, C},
title = {Targeting the Nrf2 Signaling Pathway: A Review of Traditional Chinese Medicine for Alzheimer's Disease.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-29},
doi = {10.1142/S0192415X26500400},
pmid = {42299502},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by [Formula: see text]-amyloid (A[Formula: see text]) deposition, Tau protein hyperphosphorylation, and chronic neuroinflammation. Current pharmacological interventions demonstrate limited therapeutic efficacy. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a pivotal regulator of oxidative stress and neuroinflammation, plays a critical role in AD pathogenesis. Recent studies have revealed that traditional Chinese medicines (TCMs) and their bioactive constituents can modulate the Nrf2 signaling pathway to mitigate oxidative stress, suppress neuroinflammation, enhance A[Formula: see text] clearance, and reduce Tau protein phosphorylation. By doing so, TCMs exert multi-targeted anti-AD effects. This review systematically summarizes the mechanisms and recent advances concerning the active ingredients of Nrf2 pathway-modulating TCMs, herbal medicines, and TCM formulations for the prevention and treatment of AD. Furthermore, it critically evaluates current research limitations and prospects for future research directions to provide a theoretical foundation for the development of novel anti-AD therapeutics derived from TCMs.},
}

@article {pmid42299696,
year = {2026},
author = {Brisendine, MH and Nieves-Esparcia, DQ and Willoughby, OS and Brown, B and Brown, JR and Braxton, DS and Henry, SN and McCoin, CS and Thyfault, JP and Morris, JK and Poelzing, S and Grange, RW and Jarome, TJ and Najt, CP and Drake, JC},
title = {Age-Dependent Remodeling of the Sciatic Nerve Proteome in 5xFAD Mice Can Be Attenuated by Exercise or Donepezil Treatment to Maintain Neuromuscular Function.},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70595},
pmid = {42299696},
issn = {1474-9726},
support = {R01AG080731/AG/NIA NIH HHS/United States ; K02AG088474/AG/NIA NIH HHS/United States ; R00AG070104/AG/NIA NIH HHS/United States ; R01AG062548/AG/NIA NIH HHS/United States ; R01AG069781/AG/NIA NIH HHS/United States ; P20GM144269/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Donepezil/pharmacology/therapeutic use ; Mice ; *Proteome/metabolism ; *Sciatic Nerve/metabolism/drug effects ; *Physical Conditioning, Animal ; *Aging ; Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy ; Muscle, Skeletal/drug effects ; Male ; },
abstract = {Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline. Although AD is primarily an age-related brain pathology, increasing evidence indicates dysfunction in peripheral nerves and skeletal muscle may manifest early in the disease progression. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood. Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months, identifying proteome remodeling coincides with functional declines at 4 months particularly in pathways linked to mitochondrial turnover, calcium handling, and inflammation. We hypothesized either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates, were given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil. We assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in vivo at 4 months. Both exercise and donepezil attenuated in vivo nerve-stimulated muscle torque and CNAP dysfunction. Further, both exercise and donepezil attenuated the proteomic remodeling of the sciatic nerve through both shared and independent mechanisms that converged on mitochondria-centric pathways. Our findings in the 5xFAD model of AD support the notion that early phenotypes of AD are evident in the periphery that may have implications for timing of interventions.},
}

Animals
*Donepezil/pharmacology/therapeutic use
Mice
*Proteome/metabolism
*Sciatic Nerve/metabolism/drug effects
*Physical Conditioning, Animal
*Aging
Mice, Transgenic
*Alzheimer Disease/metabolism/drug therapy
Muscle, Skeletal/drug effects
Male

@article {pmid42299743,
year = {2026},
author = {Bélanger, E and Couch, E and Carroll, M and Gadbois, EA and Jutkowitz, E and Van Houtven, CH and Wetle, TT},
title = {Long-Term Perceptions of the Value of Amyloid PET Scans Among Cognitively Impaired Medicare Beneficiaries and Their Care Partners.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {6},
pages = {e70226},
doi = {10.1002/gps.70226},
pmid = {42299743},
issn = {1099-1166},
support = {R01AG053934/NH/NIH HHS/United States ; //American College of Radiology Imaging Network/ ; /ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Positron-Emission Tomography/psychology/economics ; Male ; Female ; Aged ; United States ; Aged, 80 and over ; Medicare ; *Alzheimer Disease/diagnostic imaging ; *Caregivers/psychology ; Qualitative Research ; *Cognitive Dysfunction/diagnostic imaging ; Amyloid ; },
abstract = {OBJECTIVES: The objective of this study was to examine the long-term perceptions of the value of receiving an amyloid PET scan, a test used to diagnose Alzheimer's disease, among Medicare beneficiaries with cognitive impairment and their care partners.

METHODS: An exploratory qualitative research design was used. A total of 100 in-depth semi-structured interviews were conducted with a purposeful sample of CARE-IDEAS participants two to three years post-scan. A team of coders applied qualitative content analysis to identify content about the value of the scan, which was then analyzed using thematic analysis, and stratified by diagnostic category (mild cognitive impairment vs. dementia) and scan results (elevated amyloid vs. not elevated).

RESULTS: A majority of amyloid PET scan recipients and their care partners emphasized major benefits of receiving the scan including increased certainty about diagnosis, the ability to prepare for the future, potentially accessing treatment or trials, the ability to contribute to research, and limited procedural risks. Some participants also reported concerns about the cost of the scan, the lack of effective treatment options and clear prognostic information, the limited impact on their lives or treatment plans, and the emotional toll of living with the results. Their views and endorsements of the scan were shaped by their health and personal circumstances (e.g., seen as less relevant among those with rapidly declining health), and by their preference for more information and involvement in decision-making.

CONCLUSION: The perspectives of persons living with cognitive impairment and their care partners about the value of amyloid PET scans differed across disease trajectories and personal circumstances. These experiences should be taken into consideration when advising symptomatic patients on the benefits and drawbacks of biomarkers for Alzheimer's disease.},
}

Humans
*Positron-Emission Tomography/psychology/economics
Male
Female
Aged
United States
Aged, 80 and over
Medicare
*Alzheimer Disease/diagnostic imaging
*Caregivers/psychology
Qualitative Research
*Cognitive Dysfunction/diagnostic imaging
Amyloid

@article {pmid40553395,
year = {2025},
author = {Xu, Z and Zhu, Y and Liu, L and Liu, C and Zhang, Z and Li, M and Yao, L and Wang, F and Dong, Z and Gao, S and Kang, L and Shi, L},
title = {An analysis of the therapeutic efficacy and underlying mechanisms of combining lycopene with dental pulp stem cells to ameliorate alzheimer's disease in rats.},
journal = {Metabolic brain disease},
volume = {40},
number = {6},
pages = {233},
doi = {10.1007/s11011-025-01661-3},
pmid = {40553395},
issn = {1573-7365},
abstract = {The choroid plexus (CP), which is responsible for forming the blood-cerebrospinal fluid barrier, contributes to the modulation of deficits in Alzheimer’s disease (AD) by enhancing neuroinflammatory and brain immune responses. Previous research has demonstrated that lycopene (LYCO) or dental pulp stem cells (DPSCs) can attenuate AD-related inflammatory responses. However, it remains unclear whether LYCO and DPSCs can synergistically ameliorate neuroinflammation in the CP. Therefore, this study aims to investigate the feasibility of combining LYCO with DPSCs to mediate immunomodulatory effects within the CP in a rat model of AD. The findings indicated that oral administration of LYCO, transplantation of DPSCs, and the combination of these two methods significantly enhanced the learning and memory capabilities of AD rats in the water maze test, including improvements in directional sense and spatial orientation abilities. Furthermore, these treatments were associated with a reduction in pro-inflammatory mediators (TNF-α and IL-1β) and an increase in anti-inflammatory mediators (IL-10 and TGF-β1) within cerebrospinal fluid and hippocampal tissue. Furthermore, treatment with LYCO, DPSCs, or their combination effectively reverses Aβ1−42-induced upregulation of Toll-like receptor 4 expression at both mRNA and protein levels, as well as the expression of NF-κB p65. This study presents novel experimental evidence supporting the combined therapeutic potential of LYCO and DPSCs in modulating immune responses within the CP, while also offering valuable insights into the pathophysiology of AD and potential mechanisms associated with CP.},
}

@article {pmid40571874,
year = {2025},
author = {Qadir, H and Hussain, SH and Ghaffar, A and Shah, FA and Ahmed, S},
title = {Targeting Fyn Kinase for Alleviation of Cognitive Impairment in Streptozocin-Induced Alzheimer's Disease in Mice by Loperamide; An Experimental and in Silico Analysis.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {212},
pmid = {40571874},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder that leads to irreversible deterioration of neuronal cells over time. It is the most frequent cause of dementia in elderly individuals globally. Current treatment drugs exhibit modest effect on AD patients. Fyn kinase is implicated in AD pathogenesis, and its interactions with both AD hallmarks Aβ and tau make it a unique therapeutic target. To explore small molecule inhibitors effective in treating AD, FDA-approved drugs were evaluated using molecular docking to determine their affinity for Fyn kinase. The findings of molecular simulations support the repurposing of loperamide for treating AD. Swiss albino mice were divided into six groups, including sham control, STZ group, donepezil-treated positive control, and three loperamide-treated groups with varying doses (2.5, 5, 10 mg/kg). Cognitive functions were assessed using Novel Object Recognition (NOR), Morris Water Maze (MWM), and Elevated plus Maze (EPM) tests. Histological analyses were performed using Congo red, haematoxylin-eosin, and nissl staining. Gene expression of AD markers including Fyn, App, tau, Dlg4, Gfap, Bdnf, Cal1, Ide, Nep, and Sv2a were evaluated using qPCR. For protein quantification, amyloid beta 42 levels were measured using ELISA, while tau phosphorylation was assessed by immunohistochemistry. Our results show that loperamide treatment significantly improved cognitive function in mice, reduced amyloid accumulation and neuronal loss, and enhanced Aβ clearance most probably by upregulating Nep and Ide. Additionally, qPCR results revealed a significant decrease in Fyn expression. Amyloid beta 42 levels were significantly reduced by loperamide treatment, accompanied by decreased phosphorylated tau immunoreactivity in the cortex, dentate gyrus, and cornu ammonis 1 region. We conclude from these investigations that loperamide may serve as a promising therapeutic agent for AD by potentially targeting Fyn kinase, suggesting that further research is needed to explore its effectiveness in treating AD.},
}

@article {pmid41212305,
year = {2026},
author = {Li, Z and Jia, L and Huai, S},
title = {Bidirectional causal association between cathepsins and neuropsychiatric disorders: univariate and multivariate Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1775-1787},
pmid = {41212305},
issn = {1433-8491},
abstract = {BACKGROUND: Neuropsychiatric disorders are among the most common diseases worldwide and are characterized by complex pathogenic mechanisms. Cathepsins (CTS) are crucially involved in the pathogenesis and treatment of numerous diseases. Increasing evidence suggests a relationship between cathepsins and neuropsychiatric disorders. However, the causal associations remain unclear. METHODS: We performed a bidirectional two-sample Mendelian randomization (MR) analysis, applying univariable (UVMR) and multivariable MR (MVMR) to evaluate the causal association between nine cathepsins and five neuropsychiatric disorders. Data for this study were derived from genome-wide association studies (GWAS). The MR analysis primarily used five methods: Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger regression, Simple mode, and Weighted mode. Additionally, sensitivity tests were employed to assess the robustness of the MR results. RESULTS: MR analyses indicated that CTSH is associated with an increased risk of Alzheimer’s disease (AD) (UVMR: OR, 1.041; 95% CI, 1.013–1.069; p = 0.004; MVMR: OR, 1.040; 95% CI, 1.014–1.066; p = 0.003; replication UVMR: OR, 1.046; 95% CI, 1.014–1.082; p = 0.011). Findings that were significant in only one MR approach, such as the putative causal effects of CTSF on AD and bipolar disorder (BIP), of CTSL2 on major depressive disorder (MDD), and of CTSH and CTSE on Parkinson’s disease (PD) should be interpreted with caution. CONCLUSION: CTSH can be considered a plasma biomarker for AD, offering new insights and potential directions for the prevention and treatment of AD. Additionally, during the treatment of BIP and PD, attention should be paid to CTSF and CTSE expression levels to maintain physiological homeostasis.},
}

@article {pmid41372737,
year = {2025},
author = {Shah, A and Doshi, G},
title = {Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41372737},
issn = {2240-2993},
abstract = {Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis are strongly influenced by persistent stress, which accelerates both their onset and progression. This review explores the intricate interplay between chronic stressors, oxidative and metabolic imbalances, protein misfolding, inflammatory responses, and psychosocial adversity, and their cumulative impact on the aging brain’s capacity for homeostasis. The loss of cellular resilience due to prolonged stress leads to maladaptive outcomes, including mitochondrial dysfunction, sustained neuroinflammation, breakdown in proteostasis, and disruption of hypothalamic-pituitary-adrenal axis signaling, all of which amplify neuronal vulnerability. The detailed molecular pathways that underlie these phenomena, the article identifies key mediators such as Reactive Oxygen species, mitochondrial regulators, heat shock proteins, and proinflammatory cytokines that drive neurodegeneration. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar up to 2025. Eligible publications included original research articles, clinical studies, and systematic reviews focusing on stress-related molecular pathways, oxidative metabolism, proteostasis, neuroinflammation, and therapeutic interventions in aging and neurodegenerative diseases. A qualitative synthesis of these studies was performed to identify key mechanisms, biomarkers, and emerging treatment strategies relevant to stress-induced neurodegeneration. Further, the review evaluates both established and emerging interventions aimed at mitigating these stress-driven processes. Lifestyle modifications such as aerobic exercise, calorie restriction, and cognitive behavioural therapies complement pharmacological agents like antioxidants, chaperone modulators, and anti-inflammatory drugs to enhance brain resilience and delay disease onset. Recent advances in the field, including integrated multi-omics profiling, biomarker discovery, and medicine approaches, promise to refine our ability to satisfy patients and deliver targeted therapies based on individual stress profiles. Additionally, the article discusses the neuroimmune-gut axis and the potential for interventions targeting microbiome-related inflammation. Early detection of stress-related biomarkers and personalized strategies holds considerable promise for improving clinical outcomes, enabling earlier diagnosis, and fostering tailored therapies that preserve cognitive function and independence in aging populations.},
}

@article {pmid41575555,
year = {2026},
author = {Yu, S and Ye, Z and Zhao, W and Yu, X and Qiu, Y and Lin, K and Lu, T and Ge, L and Sun, J and Hua, R},
title = {Genetic evidence on chemical communication between gut microbiota and neurological and psychiatric disorders: a Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1759-1773},
pmid = {41575555},
issn = {1433-8491},
support = {2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; YN2018ZD04and2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; },
abstract = {BACKGROUND: Accumulating evidence from clinical trials and preclinical studies revealed the importance of the microbiota-gut-brain axis (MGBA) in neurological and psychiatric disorders (NPDs). MGBA remains a blueprint for extended explorations. METHODS: We examine the bidirectional association between 5 NPDs (late-onset Alzheimer’s disease (AD), migraine, autism spectrum disorder (ASD), all anxiety disorder, depression) and gut microbiota (GM) via microbial-derived metabolites, neurotransmitter, and precursors including total branched-chain amino acids (BCAA), isoleucine, leucine, valine, acetate, tryptophan, kynurenine, glutamate, tyrosine, serotonin using two step Mendelian randomization. Five methods were performed, including inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. The robustness of results was supported by Cochran’s Q test, the MR-Egger regression, the MR pleiotropy residual sum and outlier, and the leave-one-out method. RESULTS: After false discovery rate correction, we found elevated isoleucine in plasma as a risk factor for AD and elevated tyrosine in plasma as a risk factor for anxiety. Conversely, AD has genetically effect on a lower level of total BCAA, isoleucine, leucine, valine, glutamate, and tyrosine in plasma. We also found that Clostridia, Clostridiales, Sutterella, and Ruminococcus torques group were positively correlated with isoleucine. Elevated Sutterella abundance was found strongly positively correlated with ASD. Desulfovibrionales and Desulfovibrionaceae were found strongly positively correlated with AD. Pathways of Clostridia/Clostridiales/Ruminococcus torques group/Sutterella- isoleucine- AD were established with mediating percentages ranging from − 54.265% to 132.908%. CONCLUSION: Our study elucidates how chemical signalling bridges communication between GM and NPDs, paving avenues for microbiota-based treatment.},
}

@article {pmid41603981,
year = {2026},
author = {Raswanthiya, SP and Fernandes, OP and Mathew, MP and Balgote, PJ and Sivaraman, J},
title = {Decoding BDNF in neurodevelopmental, neurodegenerative, and neurological disorders: mechanisms and therapeutic perspectives.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {330},
pmid = {41603981},
issn = {1573-4978},
abstract = {Brain-Derived Neurotrophic Factor (BDNF) is an essential neurotrophin involved in neuronal survival, synaptic plasticity, and neurogenesis, critical for normal brain function as well as the pathology of neurological and psychiatric disorders. It primarily functions by activating TrkB receptors, which subsequently modulate intracellular signalling pathways such as PI3K-Akt, Ras-MAPK, and PLC-γ1. The expression of BDNF is precisely controlled by genetic, epigenetic, and transcriptional mechanisms, with environmental and activity-dependent factors providing further modulation. However, it is worth noting that BDNF dysregulation has been linked to major diseases such as depression, schizophrenia, autism spectrum disorder, epilepsy, Alzheimer’s disease (AD), and Parkinson’s disease (PD), and depression, with growing evidence supporting its use as a biomarker for disease monitoring and treatment. This review provides a comprehensive overview of BDNF synthesis, regulation, and signalling mechanisms, highlighting its context-dependent roles in both health and disease. It also examines the role of BDNF in cerebellar development, specifically its effects on granule cells, Purkinje cells, and interneurons govern neuronal survival, migration, and synaptic refinement, and its disruption may predispose to neuropsychiatric vulnerability. While BDNF modulation correlates with clinical outcomes, it remains unclear whether BDNF upregulation directly contributes to therapeutic efficacy or is merely an associated response. BDNF shows promise as a diagnostic biomarker and therapeutic target, merging mechanistic and clinical insights, but requires further research for full potential in precision medicine.},
}

@article {pmid41636819,
year = {2026},
author = {Fu, H and Feng, J and Zhang, X and Tian, L and Sun, S and Bo, H and He, C and Wang, X},
title = {Memantine mitigates radiation-induced cognitive impairment by modulating AKT/GSK3β signaling.},
journal = {Radiation and environmental biophysics},
volume = {65},
number = {1},
pages = {257-269},
pmid = {41636819},
issn = {1432-2099},
support = {NO.HYZHXM02004//State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center/ ; xcxjh20230610//Foundation of the Graduate Innovation Center, Nanjing University of Aeronautics and Astronautics/ ; },
abstract = {Memantine hydrochloride (MH), primarily employed in the clinical treatment of Alzheimer’s disease (AD), has been reported to exert beneficial effects on radiation-induced cognitive impairment; however, its underlying mechanisms have not been fully elucidated. In this study, a mouse model of radiation-induced injury was established. ICR(Institute of Cancer Research) mice were divided into six groups: control, 8 Gy irradiation, prophylactic 20 mg/kg + 8 Gy, prophylactic 40 mg/kg + 8 Gy, post-irradiation 8 Gy + 20 mg/kg, and post-irradiation 8 Gy + 40 mg/kg. Behavioral assessments indicated that ionizing radiation induced spatial cognitive deficits, which were ameliorated by MH administration. Morphological analyses revealed neuronal damage, synaptic injury, and demyelination in the hippocampal dentate gyrus (DG) region, which were markedly attenuated following MH treatment. Western blot analysis demonstrated that radiation upregulated dopamine D2 receptor (D2R) and β-arrestin 2 expression, suppressed PP2A expression, promoted AKT dephosphorylation, and led to GSK3β overactivation, along with increased expression of MBP and PLP1—potential mechanisms underlying radiation-induced cognitive impairment. MH administration downregulated D2R and β-arrestin 2, enhanced PP2A-AKT interaction, reduced GSK3β activity, and upregulated MBP and PLP1 expression. Notably, prophylactic administration conferred greater neuroprotection than post-irradiation treatment. These findings provide preliminary insight into the protective mechanisms of MH against radiation-induced cognitive impairment and offer a basis for future studies in radiation neuroprotection.},
}

@article {pmid41701395,
year = {2026},
author = {Nisar, A and Akhter, N and Chauhdary, Z and Anjum, F and Saleem, F and Sana, S and Rafiq, I and Mustafa, A},
title = {Investigating the Neuroprotective Effects of Saw Palmetto Fruit Extract Against D-Galactose and Aluminum Chloride Induced Alzheimer's Disease: In Vivo Study.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {76},
pmid = {41701395},
issn = {1573-6903},
abstract = {Serenoa repens (Saw palmetto) contain 85–90% fatty acids and other constituents include sterols rich in components as carotenoids, lipases, tannin and sugars. The purpose of this study is to investigate the therapeutic potential of Saw palmetto fruit extract against Alzheimer’s disease in a mice model. Phytochemical analysis was performed by HPLC analysis after preparation of plant extract by microwave assisted extraction technique.AD induced in mice by D-galactose and aluminum chloride 100 mg/kg of each (orally), and treated with saw palmetto fruit extract 250 mg/kg, 500 mg/kg, and 800 mg/kg were administered orally for 21 days. Neurobehavioral observations were performed to determine the pharmacological manipulation on cognitive and behavioral functions. Mice were sacrificed after behavioral studies to perform biochemical, neurochemical and gene expression analysis. Neuro-active compounds detected in HPLC analysis like chlorogenic acid, p-coumaric acid, gallic acid, HB acid and salicylic acid were screened by the molecular docking and interaction analysis. SP extract treatment showed dose-dependent neuroprotective effects as manifested by neurobehavioral, histopathological analysis which showed that with 250 mg/kg moderately enhance the synaptic density and neuronal survival. Notable neurodegenerative effects were observed at 800 mg/kg, accompanied by reduced neurodegenerative histopathology at 500 mg/kg. Phytochemicals in SP extract showed most stable conformation within the active site of target protein AChE. ADMET results sustained the computational experiments by presenting significant results, further molecular dynamic analysis also confirms the perfect interaction of the target AChE protein with Quercetin, Chlorogenic acid. These five phytochemicals could be recommended for clinical testing for management of Alzheimer’s disease.},
}

@article {pmid41746530,
year = {2026},
author = {Jadhav, VP and Mohanty, PK},
title = {Neuroprotective Effects of Citropten Against Scopolamine-Induced Cognitive Impairment and Oxidative Stress in a Rat Model.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41746530},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a chronic and progressive neurological degeneration marked by cognitive impairment and memory deficits, with oxidative stress and disturbances in the cholinergic system serving as key pathological factors. The current investigation sought to evaluate the neuroprotective and cognition-enhancing properties of Citropten (5,7-dimethoxycoumarin), a bioactive compound belonging to the coumarin class, in a scopolamine-induced cognitive impairment model. Wistar rats were divided into vehicle control, scopolamine alone, standard drug, and two Citropten-treated groups (12.5 and 25 mg/kg), and treated orally once daily for 18 days. Cognitive impairments were induced by daily scopolamine administration (2 mg/kg, i.p.) from Day 8 onward. Behavioral performance was analysed with the Novel Object Recognition (NOR), Elevated Plus Maze (EPM) and Morris Water Maze (MWM). Post-behavioral testing, brain tissues were analysed for acetylcholinesterase (AChE) activity, level of malondialdehyde (MDA), reduced glutathione (GSH), and catalase (CAT) activity. Scopolamine significantly impaired spatial, and recognition memory, as well as EPM-based learning memory performance, increased AChE activity and MDA levels, and reduced GSH and CAT activity compared with vehicle control group. Citropten treatment dose-dependently improved escape latency and target quadrant time spent in the MWM, enhanced the discrimination index in NOR test, and reduced transfer latency in the EPM. Biochemically, Citropten significantly reduced AChE and MDA levels while restoring GSH and CAT activity, showing effects comparable to the standard drug, Donepezil. Our findings demonstrate that Citropten exhibits multi-targeted neuroprotective agent, with potential relevance for mitigating cognitive dysfunction associated with cholinergic and oxidative stress pathways in scopolamine-induced cognitive impairment model.},
}

@article {pmid41758263,
year = {2026},
author = {Movaffagh, S and Behzadifard, M and Moghaddasi, M and Nazarinia, D and Jafaripour, L},
title = {Kinetin mitigate neurodegenerative damage of Alzheimer induced by beta-amyloid in male rats by antioxidant and antithrombotic effects.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41758263},
issn = {1573-7365},
abstract = {Alzheimer’s disease (AD) is a neurodegenerative disease that is charactrized by impaired memory and cognitive function. Kinetin (Kn) is a drug that possesses antioxidant and antithrombotic properties. This study aimed to evaluate the effects Kn as a potential treatment for AD in a rat model. Thirty-five Wistar rats were randomly divided into five groups: sham, Aβ, Aβ + 0.5 mg/kg Kn, Aβ + 1 mg/kg Kn, and 1 mg/kg Kn. Beta-amyloid was administered via bilateral intraventricular injection of 10 µl. KN was injected intraperitoneally for two weeks. Subsequently, behavioral tests were conducted, and plasma was used for the thrombolytic test. Hippocampal tissue was analyzed for oxidative stress markers, inflammatory cytokine expression, apoptosis-related gene expression, and neuronal damage. In the Aβ group, behavioral tests demonstrated impaired memory. Levels of plasminogen activator inhibitor-1 (PAI-1), malondialdehyde (MDA), the expression of tumor necrosis factor-alpha (TNF-α) and BAX genes, and the number of degenerated neurons in the hippocampus were significantly increased compared to the sham group. Conversely, glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), plasma tissue plasminogen activator (t-PA) level, and bcl-2 gene expression were significantly decreased in the Aβ group relative to sham controls. Treatment with kinetin improved memory performance and significantly reduced plasma level of PAI-1, MDA, and TNF-α, BAX expression, and neuronal degeneration. Additionally, kinetin significantly increased GSH, SOD, CAT, t-PA levels, and bcl-2 gene expression. Our study showed that kinetin, especially at a dose of 1 mg/kg, with its antioxidant and antithrombotic properties, reduces hippocampal tissue damage following Aβ-induced Alzheimer’s disease, thereby alleviating memory and learning impairments in rats.},
}

@article {pmid41831181,
year = {2026},
author = {Jankowski, WM and Fichna, J and Tarasiuk-Zawadzka, A},
title = {Can Nutrition Modulate the Progression of Alzheimer's Disease? A Narrative Review.},
journal = {Current nutrition reports},
volume = {15},
number = {1},
pages = {},
pmid = {41831181},
issn = {2161-3311},
support = {#503/1-156-04/503-11-001//Uniwersytet Medyczny w Lodzi/ ; },
abstract = {PURPOSE OF REVIEW: Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the nervous systems, along with the accumulation of abnormal proteins in brain structures. The most common neurodegenerative disease is Alzheimer’s disease (AD), which manifests as memory loss, cognitive deficits, communication difficulties, personality changes and impaired ability to perform daily activities. The purpose of this study is to gather available information on the relationship between dietary habits and the pathogenesis of AD. RECENT FINDINGS: A growing body of scientific literature points to the important influence of diet and its nutrients on the mechanisms of AD development. Polyphenols play a key role in reducing oxidative stress and inflammation in the brain. B vitamins, as well as vitamins A, C, D and E, help protect neurons and improve cognitive function. In addition, omega-3 fatty acids, inhibit the formation of amyloid beta deposits and reduce hyperphosphorylation of tau protein. It is worth noting that the Mediterranean diet has shown beneficial effects on brain health, in contrast to the Western diet, which promotes the development of these conditions. Recent studies also emphasize the role of the gut microbiota and its metabolites, such as short-chain fatty acids, as factors involved in preventing the development of AD. A balanced diet, such as the Mediterranean diet, rich in antioxidants, anti inflammatory components and supportive of a healthy gut microbiome, can slow the progression of AD and serve as a complementary approach to its treatment.},
}

@article {pmid41854817,
year = {2026},
author = {Yang, H and Fu, R and Duan, Y and Hua, Y and Wei, T and Li, G and Gu, X and Li, M and Yu, X and Li, L and Cao, L and Wang, ZZ and Zhang, C and Lv, Y and He, M and Xiao, W},
title = {Tubuloside B Alleviates Aβ25-35 Induced PC12 Cell Injury by Attenuating Pyroptosis, Apoptosis and Excessive Autophagy.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41854817},
issn = {1476-3524},
support = {2440STCZB2614//industrial foundation reengineering and high-quality development of manufacturing industry/ ; },
abstract = {Cistanche, a traditional Chinese medicine with reported neuroprotective effects, contains multiple bioactive constituents whose specific mechanisms of action remain incompletely defined. Here, we aimed to identify a key neuroprotective component and explore its potential mechanism against Aβ-induced neurotoxicity. Fourteen commercially available Cistanche-derived compounds were screened for neuroprotection in an Aβ25-35 (Aβ fragment 25–35)-injured PC12 cell model. The most active compound, Tubuloside B (TB), was further investigated using polymerase chain reaction (PCR) array, immunoblotting, flow cytometry, immunofluorescence, and mitochondrial function assays. TB exerted concentration-dependent protective effects in the Aβ25-35-injured PC12 model. Aβ25-35 exposure was associated with marked activation of pyroptotic signaling, characterized by caspase-1 activation, GSDMD cleavage, and increased interleukin (IL)-1β/IL-18 levels. These alterations were substantially blunted in the presence of TB. Modulation of the absent in melanoma 2 (AIM2) inflammasome pathway was further supported by reduced AIM2 expression and diminished apoptosis-associated speck-like protein containing a CARD (ASC) speck formation. Mitochondrial perturbations induced by Aβ25-35, including excessive mitochondrial reactive oxygen species (ROS) generation, membrane depolarization, and cytosolic mtDNA accumulation, were concurrently ameliorated by TB. In addition, markers of apoptosis and dysregulated autophagy were partially normalized following TB treatment. These findings suggest that TB may contribute to neuroprotection in an Aβ25-35-induced PC12 cell model, potentially involving modulation of mitochondrial dysfunction–associated inflammasome activation and downstream cell death pathways. Given the in vitro design and limited sample size, these results should be considered preliminary and warrant further validation in vivo.},
}

@article {pmid41863595,
year = {2026},
author = {Ji, J and Li, Z and Xing, A and Luo, G and Zhai, X and Xu, W and Li, J and Tan, T and Jia, R and Yan, Y and Zhang, X and Wang, L and Li, J and Li, K},
title = {Causal relationships between alzheimer's disease genetics and brain connectivity alterations: a multi-modal mendelian randomization study with transcriptomic validation of 191 rs-fMRI and 635 DTI neuroimaging traits.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41863595},
issn = {1931-7565},
support = {2023XM016//Four "Batches" Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province/ ; 0033/2023/RIB2//The Science and Technology Development Funds of Macao/ ; RP/FCA-14/2023//a Grant from Macao Polytechnic University/ ; },
abstract = {Traditional observational magnetic resonance imaging (MRI) studies have revealed changes in brain connectivity in Alzheimer’s disease (AD). However, the findings have been inconsistent due to small sample sizes and potential confounding factors. The genetic effects of AD on the inherent brain activity and connectivity of patients are still not well understood. We utilized summary-level GWAS data for 223,906 Europeans from three large AD cohorts and comprehensive GWAS data for 191 rs-fMRI functional connectivity (FC) traits (n = 34,691) and 635 diffusion tensor imaging (DTI) metrics (n = 33,292) from the BIG Knowledge Portal. A bidirectional two-sample Mendelian randomization (MR) analysis with multiple MR methods was performed to evaluate the causality between AD genetics and genetically predicted whole-brain functional and structural connectivity changes. A series of sensitivity analyses were systematically conducted to assess the pleiotropy, heterogeneity, and outliers. Additionally, SNP-to-gene mapping, enrichment analysis, protein-protein interaction (PPI), single-SNP, and SNP location-based MR were performed to elucidate the molecular mechanisms. To validate our findings, we analyzed an independent cohort from ADNI (n = 30/group) and performed transcriptomic validation using RNA-seq data from 63 samples (32 AD, 31 control). Our MR analysis revealed significant causal associations between AD and specific alterations in fMRI FC, particularly involving the precuneus, occipital lobe, and default mode network. Similarly, AD was causally linked to changes in fractional anisotropy (FA) and mean diffusivity (MD) across distinct white matter fiber tracts. The molecular mechanisms underlying these MRI changes involved polygenic contributions from multiple AD-associated SNPs, primarily those mapped to non-coding regions, in addition to genic SNPs enriched in pathways regulating amyloid-beta clearance and neuroinflammation. External validation using the ADNI cohort confirmed the FC alterations identified through MR. Transcriptomic validation confirmed the significant upregulation of four genes (CTSB, SDC4, CTNND2, and FERMT2) in AD and uncovered three potential AD-associated genes (ITGB1BP1, FBXO33, and RASGEF1C). Our multi-modal MR study elucidated causal links between AD genetics and brain imaging-derived phenotypes (IDPs), with independent validation from both neuroimaging and transcriptomic analyses. These findings enhance understanding of AD etiology and identify potential MRI markers for diagnosis and treatment monitoring.},
}

@article {pmid41863703,
year = {2026},
author = {Al-Kuraishy, HM and Jabir, MS and Rafeeq, MF and Sulaiman, GM and Albuhadily, AK and Al-Gareeb, AI},
title = {Targeting of neuroinflammation, oxidative stress, and synaptic dysfunction by vinpocetine in alzheimer's disease: a comprehensive appraisal.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863703},
issn = {1573-7365},
abstract = {Alzheimer disease (AD) is a neurodegenerative disease presented with progressive memory loss and cognitive impairment. Deposition of extracellular amyloid beta (Aβ) peptide and intracellular neurofibrillary tangles (NFTs) are the hallmarks of AD neuropathology. Progressive accumulation of Aβ and NFTs results in the development of inflammation/ neuroinflammation, oxidative stress, synaptic failure, neuronal apoptosis, and the development of AD. However, no single drug is effective as disease modifying treatment for AD, as many cellular and molecular signaling pathways beyond Aβ and NFTs are involved in AD neuropathology. Mounting evidences indicated that phosphodiesterase enzymes (PDEs) mainly PDE1 are involved in AD neuropathology. PDEs are intricate in the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are reduced in AD. Consequently, this review aims to revise the role of PDEs, and PDE1 selective inhibitor vinpocetine (VPN) in AD neuropathology. VPN by its anti-inflammatory and antioxidant effects can reduce inflammatory and oxidative stress in AD correspondingly. At molecular levels, VPN by targeting peroxisome proliferator activated receptor γ coactivator 1 α (PGC1α), brain derived neurotrophic factor (BDNF) and SIRT1 can mitigate AD neuropathology. Despite of these evidences, however there is limited clinical evidence for the efficacy of VPN in AD. Therefore, large-prospective clinical studies are warranted in this regard.},
}

@article {pmid41863721,
year = {2026},
author = {Maidh, A and Kalra, P and Khan, H and Silakari, P and Grewal, AK},
title = {Circadian disruption as a driver and target in neurodegenerative diseases: from molecular mechanisms to chronotherapeutic strategies.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863721},
issn = {1573-7365},
abstract = {The Circadian System is a complex network of coordinated clocks that regulates the organism’s internal clock in synchronisation with the outside world. These rhythms are controlled by genetically controlled positive and negative transcriptional-translational feedback loops (TTFL) that generate 24-hour oscillations in the protein level and mRNA of core circadian components. Circadian disruption is recognised as a significant contributor to the molecular pathogenesis of neurodegenerative illnesses, as disease-specific alterations in clock gene expression and melatoninergic signalling have been identified as possible early-stage molecular indicators. Emerging evidence suggests a link between dysregulated circadian rhythms and neurodegenerative diseases, implying that the changes in circadian function may play a critical role in the development and progression of neurodegenerative diseases. The correlation between circadian rhythm and neurodegeneration is highly promising for developing treatment and promoting healthy lifestyle measures. This review article primarily focuses on how abnormalities in circadian rhythms may increase the risk of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Applying knowledge from pre-clinical and translational research on neurodegenerative diseases is crucial for lowering the risks of neurodegeneration and improving the symptoms and quality of life of people with neurodegenerative diseases through approaches that restore circadian rhythm in the context of precision medicine. Understanding this interaction holds promise for developing therapeutic approaches to support a healthy lifestyle.},
}

@article {pmid41910845,
year = {2026},
author = {Nekabari, MK and Ben-Azu, B and Chijioke, BS and Esuku, DT and Chidebe, EO and Friday, FB and Usin, SG and Iwhiwhu, P and Moses, AS and Diakparomre, O and Onyeukwu, OB},
title = {Lipopolysaccharide-induced Neuroimmune Alteration and Memory Decline in Aging Mice: The Role of Augmented Cellular Senescence.},
journal = {Neurotoxicity research},
volume = {44},
number = {2},
pages = {},
pmid = {41910845},
issn = {1476-3524},
abstract = {Alzheimer’s disease (AD) remains a complex neurodegenerative disorder with multifactorial etiologies, often eluding effective modeling in preclinical studies. However, whether neuroinflammation, exacerbated by accelerated cellular senescence, is central to AD pathology induced by lipopolysaccharide, an endotoxemia agent, remains unknown. This study investigated a combination of lipopolysaccharide (LPS)-induced AD-like neuroinflammation with doxycycline-induced conditioned cellular senescence in mice. Following a 21-day doxycycline (DOXY)-induced cellular senescence in mice, neuroinflammation was induced by LPS from days 15–21. AD-related cognitive decline was investigated through spatial and non-spatial memory tests, oxidative stress, molybdoenzymes, acetylcholinesterase activity, inflammation, amyloid-beta levels, hypoxia-inducible factor (HIF-α) and brain-derived neurotrophic factors (BDNF) in brain regions affected by AD pathology, such as the hippocampus and prefrontal cortex (PFC). Behavioral assessments revealed that both LPS and DOXY independently impaired spatial and non-spatial working memory, locomotor activity, social interaction, and recognition memory, with their interactive treatment exacerbating these deficits significantly. Biochemical analyses revealed synergistic increases in pro-inflammatory cytokines (IL-1β, TNF-α, but not IL-4), oxidative stress markers (malondialdehyde, nitrite), astrocyte activation (GFAP), and amyloid-beta levels, with decreases in antioxidant defenses (GSH, GST, SOD, catalase) in the hippocampus and PFC. The DOXY + LPS group showed higher serum corticosterone levels, increased sulphite-oxidase in the PFC, and increased xanthine-oxidase and acetylcholinesterase in both regions, indicating an amplified stress response and cholinergic dysfunction. Conversely, DOXY + LPS interaction lowered hippocampal-targeted BDNF and HIF-α levels. These findings validate the role of cellular senescence in enhancing LPS-induced neuroinflammation, mimicking complex AD features, and provide a model for testing disease mechanisms and therapeutics.},
}

@article {pmid41931192,
year = {2026},
author = {Du, M and Ma, S and Bai, L and Mou, X and Gao, Y and Zhang, J and Chen, Y},
title = {Olfactory Dysfunction Exacerbates Hippocampal Aβ Accumulation, Tau Phosphorylation and Memory Deficits in Mice.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41931192},
issn = {1573-6903},
support = {202401AU070130//Natural Science Foundation of Yunnan Province/ ; 202301AT070430//Natural Science Foundation of Yunnan Province/ ; 202305AS350011//innovation team of stress and disorder in nervous system in Yunnan Province/ ; 82201597//the National Natural Science Foundation of China/ ; KUST-KH2022001Y//the Joint Medical Specialization of Kunming University of Science and Technology/ ; },
abstract = {Olfactory dysfunction is a frequent feature in patients with neurodegenerative disorders such as Alzheimer’s disease (AD). However, whether olfactory impairment is the cause or consequence of AD is unknown. We previously found that olfactory dysfunction impairs learning and memory in mice in multiple experimental paradigms, but whether olfactory dysfunction increases AD-related neuropathological changes such as Aβ deposition and tau protein phosphorylation is not clear. In this study, mice were treated with bilateral intranasal zinc sulfate (ZnSO4) solution infusion, which resulted in olfactory dysfunction for about 1 month in mice. 1, 3, 6, and 9 months after that, the Y-maze learning and memory, as well as hippocampal Aβ deposition, tau and p-tau expression were tested. We found that olfactory dysfunction leads to a long period and irreversible learning and memory impairment in mice. Olfactory dysfunction also increased Aβ deposition, Aβ42 level, and increased p-tau expression in hippocampus (HPC), which were accompanied by increased beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and decreased presenilin-1 (PS1) expression. Compared with one time of ZnSO4 treatment, repetitive ZnSO4 treatment (three times, a month apart) resulted in more significant increases in tau phosphorylation in mice hippocampus. These results suggest that olfactory dysfunction lead to behavioral and pathological changes associated with AD in mice, which suggest that olfactory dysfunction can contribute to the development of AD.},
}

@article {pmid41944966,
year = {2026},
author = {Riaz, M and Qadir, H and Noman, M and Ahmed, S and Shah, FA and Malik, MU and Bashir, K and Farooq, U and Irshad, N},
title = {Mechanistic Insights into Bergapten by Modulation of Filamin A and GSK3β in STZ Induced Alzheimer's Disease: An Integrated In Silico, In Vitro and In Vivo Study.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41944966},
issn = {1573-6903},
abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction and neuroinflammation. The study investigates bergapten (BGN) as a potential AD treatment. Computational analysis revealed strong binding affinity of BGN with Filamin A (FLNA) and glycogen synthase kinase-3β (GSK3β). In vitro assays demonstrated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition suggesting cholinergic modulation. In intracerebroventricular (i.c.v) streptozotocin (STZ) induced AD mice model, BGN (25 mg/kg, 50 mg/kg and 100 mg/kg i.p) was administered daily for 23 days. The blood and brain tissues samples were collected for biochemical and histopathological analysis. BGN showed dose-dependent cognitive improvements, with biochemical tests indicating renal and hepatic safety. Reduced C-reactive protein and lactate dehydrogenase levels suggested minimal systemic toxicity and neuroinflammation. Histology revealed preserved neurons, decreased amyloid deposits, and improved brain structure. Immunohistochemical analyses indicated BGN was associated with lower Tau, NF-κB, TLR4, and Caspase-3 expression and restored redox homeostasis. Critically, ELISA confirmed reduced FLNA along with Aβ and GSK-3β levels and thus highlights BGN novel modulation of this unexplored AD target. RT-PCR analysis showed downregulated expression of amyloid precursor protein, tau, discs large scaffold protein 4 and glial fibrillary acidic protein, while enhanced synaptic plasticity markers. Collectively, these findings suggest BGN as a promising multi-target neuroprotective and safer agent for AD.},
}

@article {pmid41945111,
year = {2026},
author = {Lai, Z and Zhang, B and Fu, Z and Li, R and Qian, Y and Zhang, Y and Xu, P and Du, Y},
title = {Research advances on Cordyceps sinensis and its components in relation to omics biomarkers for the neurological disorders.},
journal = {Die Naturwissenschaften},
volume = {113},
number = {3},
pages = {},
pmid = {41945111},
issn = {1432-1904},
support = {2026ZL0010//Zhejiang Traditional Chinese Medicine Science and Technology Program of China/ ; 82202605//National Natural Science Foundation of China/ ; 2023, DU YAOQIANG//Zhejiang Provincial Special Support Program for Cultivation of High-Level Innovative Health Talents of China/ ; },
abstract = {Cordyceps is a traditional medicinal fungus belonging to the species Ophiocordyceps sinensis. It grows in the alpine ecological zone of the Tibetan Plateau and exhibits dual characteristics of both insects and fungi. The primary species include Cordyceps sinensis and Cordyceps militaris. Rich in bioactive components such as cordycepin, polysaccharides, adenosine, and peptides, cordyceps demonstrates broad applications in immune regulation, anti-tumor activity, anti-inflammatory, and neuroprotection. Cordyceps sinensis and its components show great therapeutic potential in neurological diseases such as epilepsy, Alzheimer’s disease and Parkinson’s disease through multi-level and multi-target actions However, current research faces challenges including unclear mechanisms of action and insufficient clinical translation. In this review, we analyze the molecular mechanisms underlying cordyceps’ neuroprotective effects, including the regulating of apoptosis, improvement of mitochondrial function, and promoting of nerve repair. Utilizing network pharmacology, we explore the multi-targeted actions of cordyceps and predict the key pathways. Further we summarize the research progress in the integrated multi-omics analyses (genomics, transcriptomics, proteomics and metabolomics), to reveal the synergistic roles of cordyceps components in treating neurological disorders and identify potential molecular biomarkers. Additionally, we highlight the findings from preclinical experiments and animal models on cordyceps-based drugs, discussing their advantages and challenges for clinical application. Future studies should prioritize systematic exploration of standardized drug development, advanced multi-omics integration, and rigorous clinical trials. This will provide a more robust scientific foundation and practical guidance for the treatment of neurological diseases with cordyceps.},
}

@article {pmid42010038,
year = {2026},
author = {Nakatsuji, M and Shibano, M and Fujimori, K},
title = {Antioxidant Activity of Flavonoid Glabranin by Upregulating Antioxidant Gene Expression via MEK/ERK and PI3K/Akt Pathways in Human Neuroblastoma SH-SY5Y Cells.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42010038},
issn = {1573-6903},
support = {25ak0101219h0202//Japan Agency for Medical Research and Development/ ; },
abstract = {Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of Glycyrrhiza glabra (licorice), exhibits antioxidant and anti-inflammatory properties. However, the effect of glabranin on the antioxidant response and the underlying mechanism including the specific signaling pathways, remain unclear. In the current study, we investigated the protective effect of glabranin on hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. H2O2-induced death of SH-SY5Y cells was restored by glabranin in a concentration-dependent manner. The number of H2O2-increased apoptotic cells was reduced by co-treatment with glabranin. Moreover, glabranin attenuated H2O2-induced cleaved caspase-3/7 levels. In addition, glabranin decreased H2O2-induced intracellular ROS levels via promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 and upregulating the antioxidant gene expression. Furthermore, glabranin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) following H2O2 treatment. Inhibition of mitogen-activated protein kinase kinase (MEK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways abrogated glabranin-mediated elevation of antioxidant gene expression and neuroprotective effects. These findings suggest that glabranin mitigated H2O2-induced apoptosis by increasing the expression of antioxidant genes through activation of the MEK/ERK and PI3K/Akt pathways in SH-SY5Y cells. Therefore, glabranin has the potential to prevent and treat neurodegenerative diseases as an antioxidant agent.},
}

@article {pmid42050692,
year = {2026},
author = {Rahbek, MT and Kildegaard, H and Hallas, J and Ernst, MT and Lund, LC},
title = {Acetylcholinesterase inhibitors and the risk of delirium - a Danish nationwide register-based cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02060-1},
pmid = {42050692},
issn = {1758-9193},
abstract = {BACKGROUND: Delirium is frequent in people with dementia and is linked to adverse outcomes. Disturbed cholinergic neurotransmission is implicated in its pathophysiology. We examined whether continuous use of acetylcholinesterase inhibitors (AChEIs) is associated with a reduced risk of incident delirium in patients with dementia. METHODS: Using Danish nationwide registries (2005–2024), we identified individuals ≥ 50 years initiating AChEIs. Continuous users (second prescription within 90 days) were compared with early discontinuers. Follow-up started 90 days after initiation and continued for up to 3 years. The outcome was a hospital discharge diagnosis of delirium (ICD-10 F05). Confounding was addressed using high-dimensional propensity score (hdPS) fine-stratification weighting, and Cox regression yielded hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 45,651 patients, 311 delirium events occurred among continuous users and 84 among early discontinuers, corresponding to incidence rates of 66 and 112 events per 10,000 person-years, respectively. The hdPS-weighted HR for delirium was 0.72 (95% CI 0.54–0.96). Results were consistent across sensitivity analyses and in patients with Alzheimer’s disease HR 0.68 (95% CI 0.48–0.96). A negative control outcome showed no association. CONCLUSIONS: Continuous AChEI treatment was associated with a lower risk of delirium. Findings support a potential benefit of maintaining therapy in routine dementia care, and possibly even in patients with minor intolerance to acetylcholinesterase inhibitors.},
}

@article {pmid42281500,
year = {2026},
author = {Rashidi, SK and Dezfouli, MA and Khalili, H and Kiani, AKD},
title = {The role of gut microbiota in the neurobiology and treatment of Alzheimer's disease.},
journal = {General physiology and biophysics},
volume = {45},
number = {2},
pages = {129-151},
doi = {10.4149/gpb_2025042},
pmid = {42281500},
issn = {0231-5882},
mesh = {Humans ; *Alzheimer Disease/therapy/microbiology/physiopathology ; *Gastrointestinal Microbiome ; Animals ; *Brain/physiopathology ; Amyloid beta-Peptides/metabolism ; Probiotics/therapeutic use ; Fecal Microbiota Transplantation ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia in the elderly population and characterized by progressive cognitive decline. The major pathological features of AD are the accumulation of extracellular amyloid-beta protein as neuritic plaques and intracellular hyperphosphorylated tau protein as neurofibrillary tangles. Studies have shown that gut microbiota are involved in several central nervous system disorders through regulation of neurotransmitter production, blood-brain barrier permeability and immune responses. The gut microbiota establishes a two-way communication between the gut and the brain through neural, endocrine, and immune pathways, which play a role in various neurological diseases, including AD. Alterations in the composition and function of the gut microbiota may influence neuroinflammation, amyloid-beta accumulation, and tau pathology. Targeting the balance of the gut microbiota through probiotics, prebiotics, and fecal microbial transplantation could be promising therapeutic approach against neurodegeneration. Understanding the complex relationship between the gut microbiota and AD pathobiology could pave the way for novel preventive and therapeutic strategies. Here, we summarized advances in the role of gut microbiota in AD pathobiology and updated rising concerns from recent reports. Moreover, the possibility of applying the capability of the gut microbiota as a promising treatment against AD has been discussed in this review.},
}

Humans
*Alzheimer Disease/therapy/microbiology/physiopathology
*Gastrointestinal Microbiome
Animals
*Brain/physiopathology
Amyloid beta-Peptides/metabolism
Probiotics/therapeutic use
Fecal Microbiota Transplantation

@article {pmid42281759,
year = {2025},
author = {Foye, G and Foye, E and Walter, S and Ptomey, LT},
title = {Research should be conducted with us, not on us: Perspectives on Alzheimer's disease clinical trials for persons with Down syndrome.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {1},
number = {4},
pages = {},
pmid = {42281759},
issn = {2997-3805},
abstract = {Life expectancy for individuals with Down syndrome (DS) has increased significantly over the past 60 years, drawing greater attention to Alzheimer's disease (AD), now the leading cause of death in this population. Despite a lifetime AD risk as high as 90%, individuals with DS have been historically excluded from AD research, exacerbating already-existing significant gaps in prevention, diagnosis, and treatment strategies. Although recent clinical trials have begun to address this, challenges in recruitment and retention persist due to accessibility barriers, safety concerns, and limited prior engagement. Meaningful inclusion requires centering the voices of both individuals with DS and their caregivers to ensure that researchers provide accessible studies, communicate with respect, and share results, which will result in greater trust in research. This perspective offers personal reflections from an adult with DS, her caregiver, and two researchers, offering practical insights for designing inclusive, respectful, and person-centered clinical trials.},
}

@article {pmid42282197,
year = {2026},
author = {Shao, Y and Yin, Y and Cheng, Y and McGeary, JE and Taveira, TH and Tsuang, DW and Logue, MW and Ayandeh, S and Ahmed, A and Zamrini, E and Zeng-Treitler, Q},
title = {Medication-Wide Association Study of Alzheimer's Disease and Related Dementias: Identifying Drug Candidates from Electronic Health Records through Explainable AI.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.02.26354752},
pmid = {42282197},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a leading cause of death and disability, and treatment options for Alzheimer's disease and related dementias (ADRD) remain limited. We applied a data-driven, mechanism-agnostic Medication-Wide Association Study Plus (MWAS+) framework to identify candidate medications associated with ADRD using longitudinal electronic health record data and explainable artificial intelligence (AI).

METHODS: We used Veterans Health Administration electronic health record data from January 1999 to May 2022. The initial study population comprised 8,424,715 Veterans aged 65 years or older. Cases were defined by ADRD-related diagnosis codes or ADRD-related medication prescriptions, and controls were free of ADRD diagnosis and ADRD-related medication use. After exclusions and matching on sex, race, age at first encounter, and duration of follow-up, the primary analytic cohort included 505,817 matched case-control pairs (1:1; 1,011,634 Veterans). Longitudinal features were extracted from historical data up to 1 year before the index date and aggregated into 1-year intervals. We developed an upgraded Hybrid Value-Aware Transformer (HVAT 2.0) to jointly learn from longitudinal and nonlongitudinal clinical data while incorporating numerical values associated with clinical concepts, including cumulative medication dose. To enhance interpretability, we applied a medication-specific impact score method to estimate model-derived associations between medication exposure and ADRD risk.

FINDINGS: The model demonstrated stable performance across data partitions, with area under the receiver operating characteristic curve values of 0.791 in the training set, 0.772 in the validation set, and 0.775 in the testing set. Metolazone and varenicline were identified as the top 2 candidate medications with negative impact scores, suggesting potentially protective associations with new-onset ADRD. The impact score was -0.196 per unit of cumulative dose for metolazone (1800 mg) and -0.134 per unit for varenicline (280 mg). Although individual-level impact scores varied, most exposed patients had negative scores, including 12,020 of 12,480 metolazone users (96%) and 8,341 of 8,786 varenicline users (95%).

IMPLICATIONS: This study demonstrates the feasibility of combining a medication-wide association framework, longitudinal dose-aware modeling, and explainable AI to identify candidate medications for ADRD from real-world electronic health record data. The findings should be interpreted as signals for hypothesis generation rather than evidence of causality. This framework may support prioritization of repurposing candidates for expert review, follow-up cohort validation, and future clinical investigation.},
}

@article {pmid42282265,
year = {2026},
author = {Kwa, E and Ogilvie, CE and Kormos, NC and Green, AJE and Smith, TK and Gunn-Moore, FJ},
title = {The inhibitors of 17β-HSD10: are they any good?.},
journal = {RSC chemical biology},
volume = {},
number = {},
pages = {},
pmid = {42282265},
issn = {2633-0679},
abstract = {The advent of the first disease-modifying therapies for Alzheimer's disease (AD) has renewed optimism for effective prevention and treatment strategies. Growing mechanistic insights indicate that AD pathogenesis is multifactorial and non-linear, better conceptualized as a circular vortex in which interconnected pathological processes reinforce one another. This complexity highlights the necessity for multiple druggable targets and combination-based therapeutic approaches. A hallmark of AD is reduced cerebral glucose utilization, revealed by positron emission tomography studies, reflecting profound metabolic disruption and mitochondrial dysfunction. Among mitochondrial candidates, 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), encoded by HSD17B10, has emerged as a protein of interest. Despite debate surrounding its substrate specificity due to conflicting in vitro data, its elevated expression in neurons and astrocytes within AD brains underscores its potential relevance. This review outlines chemical entities targeting both catalytic and non-catalytic functions of 17β-HSD10 and examines whether its inhibition offers biological efficacy and clarifies its metabolic roles in the living brain.},
}

@article {pmid42282664,
year = {2026},
author = {Fang, X and Border, JJ and Zhang, H and Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Yang, J and Hwang, SH and Morisseau, C and Hammock, BD and Fan, F and Roman, RJ},
title = {Inhibition of Soluble Epoxide Hydrolase Rescues Cognitive Deficits by Preserving Neurovascular Integrity and Attenuating Glial- and Neuropathology in Diabetic-Related Dementia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.06.01.729327},
pmid = {42282664},
issn = {2692-8205},
abstract = {Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous work also demonstrated that chronic inhibition of sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day for 9 weeks) reduced brain sEH expression, improved cortical-based long-term non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect linked to upregulation of Kir2.1 expression in cerebral capillaries. Furthermore, TPPU restored tight junction proteins (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of key pro-inflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in DM-ADRD. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation, and gliosis while protecting synaptic integrity and neuronal survival, representing a promising therapeutic strategy for DM-ADRD.},
}

@article {pmid42283246,
year = {2026},
author = {Fikry, H and Saleh, LA and Sadek, DR},
title = {Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.},
journal = {Clinical anatomy (New York, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/ca.70147},
pmid = {42283246},
issn = {1098-2353},
abstract = {Neurodegenerative diseases, which afflict millions worldwide and threaten public health, have no cure. Neurodegenerative diseases lack effective therapies, burdening society and the economy. Over the past 20 years, regenerative cell therapy (stem cell therapy) has advanced, opening novel neurodegenerative disease treatments. Thus, the current review aimed to systematically highlight experimental and clinical studies of potentially effective therapeutic strategies for stem cells and report histological, cellular, or ultrastructural outcomes following stem cell interventions in neurodegenerative diseases. PRISMA-compliant computerized literature searches of PubMed, Scopus, and Web of Science identified studies on embryonic, induced pluripotent, mesenchymal, or neural stem cells (NSCs) in neurodegenerative disease models and histological and tissue-level outcomes. Search terms included nervous system diseases, histology, neuron regeneration, stem cells, stem cell treatment, and transplantation. Peer-reviewed articles published between 2000 and 2025 were selected. Experimental animal and clinical studies that reported histological or tissue-level results after stem cell treatments were included. Eighty-six studies met the eligibility criteria, covering models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Across these studies, stem cell therapies were linked to improved neuron survival, better synaptic structure, diminished gliosis, and some restoration of tissue structure. These effects depended on the type of stem cell used, the disease model, and how the treatment was given. Overall, the evidence suggests that stem cell therapies can lead to significant histological and tissue-level improvements in neurodegenerative diseases, supporting their potential for regeneration. Further standardized and translational studies are needed to clarify the underlying mechanisms and improve treatment strategies.},
}

@article {pmid42283996,
year = {2026},
author = {Totuk, O},
title = {Amyloid-Related Imaging Abnormalities in Anti-amyloid Therapy: Clinical Implications of Kinetics for Safer Use and Risk Stratification.},
journal = {Clinical drug investigation},
volume = {},
number = {},
pages = {},
pmid = {42283996},
issn = {1179-1918},
abstract = {Anti-amyloid monoclonal antibodies have emerged as disease-modifying therapies for Alzheimer's disease. However, their broader clinical adoption is limited by amyloid-related imaging abnormalities, a key safety concern. Traditionally viewed as an unavoidable and dose-dependent adverse effect, amyloid-related imaging abnormalities often lead to treatment interruption or the exclusion of high-risk patients from therapy. Emerging evidence now suggests that amyloid-related imaging abnormalities may instead reflect a transient modifiable cerebrovascular response, primarily influenced by the kinetics of amyloid clearance rather than the absolute magnitude of amyloid removal. Recent data from titration-based dosing strategies demonstrate that gradual amyloid mobilization can significantly reduce the incidence of amyloid-related imaging abnormalities without compromising amyloid positron emission tomography responses or downstream biomarkers. This kinetic perspective may support a more nuanced re-evaluation of patient groups previously deemed unsuitable for therapy, including APOE ε4 carriers, individuals with cerebral microbleeds, and patients on antithrombotic treatment. In this Current Opinion, we propose a pragmatic clinical framework that integrates amyloid clearance kinetics, magnetic resonance imaging-based risk stratification, and individualized protocols for treatment interruption and re-challenge. By reframing amyloid-related imaging abnormalities as a modifiable clinical decision-making challenge rather than an inherent toxicity, anti-amyloid therapies may be optimized for safer use; however, whether such approaches can enable broader and more inclusive treatment strategies remains to be established in prospective studies, particularly in high-risk populations.},
}

@article {pmid42284682,
year = {2026},
author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Doré, V and Laws, SM},
title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.},
journal = {EBioMedicine},
volume = {129},
number = {},
pages = {106329},
doi = {10.1016/j.ebiom.2026.106329},
pmid = {42284682},
issn = {2352-3964},
abstract = {BACKGROUND: Accumulation of brain amyloid beta (Aβ), a key pathological hallmark of Alzheimer's disease (AD), begins decades before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which Aβ exceeds a critical threshold, may enable intervention to delay or prevent onset of AD.

METHODS: Using published genome-wide association studies (GWASs), we developed polygenic scores (PGS) for AD risk (PGSrisk) and resilience (PGSresilience), and tested whether these predicted (i) if an individual is an Aβ accumulator ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ exceeds a 20 centiloid (CL) threshold ('Age at onset of Aβ'; AAO-Aβ) in 2175 participants (1158 with AAO-Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. We also performed GWASs on these traits to develop phenotype-specific PGSs.

FINDINGS: Higher genetic risk of AD predicted increased odds of Aβ accumulation (OR = 1.16; 95% CI = 1.05-1.29; p = 0.003) and younger AAO-Aβ (β = -1.32; SE = 0.31; p = 1.63 × 10[-5]). Higher genetic resilience to AD predicted later AAO-Aβ (β = 0.91; SE = 0.29; p = 0.002) but did not predict Aβ accumulation. These associations were independent of APOE ε4 status, the strongest genetic risk factor for AD. Phenotype-specific PGSs were not significantly associated with either trait.

INTERPRETATION: Polygenic scores, alongside other risk factors, may help identify individuals at risk of accumulating Aβ, and predict the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.

FUNDING: National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).},
}

@article {pmid42288063,
year = {2026},
author = {Zhao, H and Qian, S and Wang, Y and Yang, W},
title = {Information quality of Alzheimer's disease treatment videos on TikTok and related factors: A cross-sectional study.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {152},
number = {},
pages = {112144},
doi = {10.1016/j.jocn.2026.112144},
pmid = {42288063},
issn = {1532-2653},
abstract = {BACKGROUND: The increasing reliance on mobile internet for health information necessitates a critical evaluation of content quality. This study aimed to systematically assess the quality of Alzheimer's Disease (AD) treatment-related short videos on TikTok, a leading platform for health information dissemination.

METHOD: A total of 100 CE treatment videos from TikTok, retrieved on December 20, 2025, were comprehensively evaluated using established assessment tools. Specifically, the Journal of American Medical Association (JAMA) benchmark criteriaand themodified Decision-making Information Support Criteria for Evaluating the Reliability of Non-randomised Studies (mDIS) scorewere used to evaluate thereliabilityof the video content. TheGlobal Quality Score (GQS) was used to assess theoverall quality, and the Patient Education Materials Assessment Tool for Audio Visual Content (PEMAT-A/U)was used to evaluate understandability and actionability.

RESULTS: Neurologists were identified as primary contributors of high-quality content, while videos on experimental treatments like deep cervical lymphovenous anastomosis (LVA) generally exhibited lower quality. Videos from emerging first-tier cities and those uploaded by top-tier creators demonstrated superior audience engagement and often higher content quality. A significant positive correlation was found between video duration, audience engagement metrics, and content quality scores.

CONCLUSIONS: Neurologists play a crucial role in providing reliable AD treatment information on short video platforms. There is an urgent need to improve the quality of content on experimental treatments and to encourage longer, well-referenced videos. Platforms should enhance content moderation and explicitly label experimental therapies to ensure accurate and trustworthy public health education regarding AD.},
}

@article {pmid42289507,
year = {2026},
author = {Yazi, S and Ozen, B and Buldu, B and Yalcin, E and Karakose, O and Cakmak, O and Somunkiran, S and Yananli, HR and Sehirli, US and Kirazli, O},
title = {The effect of canagliflozin on hippocampal dendrite morphology in a model of Alzheimer's disease induced by intracerebroventricular injection of streptozotocin.},
journal = {Brain structure & function},
volume = {231},
number = {6},
pages = {},
pmid = {42289507},
issn = {1863-2661},
mesh = {Animals ; *Canagliflozin/pharmacology/administration & dosage ; *Alzheimer Disease/pathology/chemically induced/drug therapy ; Male ; Streptozocin/administration & dosage ; *Dendrites/drug effects/pathology ; Rats ; *Hippocampus/drug effects/pathology ; Disease Models, Animal ; Donepezil/pharmacology ; Dendritic Spines/drug effects/pathology ; Pyramidal Cells/drug effects/pathology ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Rats, Wistar ; Rats, Sprague-Dawley ; },
abstract = {Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathophysiological features. However, the effects of antidiabetic drugs on neurodegeneration are not completely known. Canagliflozin, a novel option for DM treatment, is a dual inhibitor of sodium glucose co-transporter type 2 (SGLT2) and acetylcholinesterase. The aim of this study is to examine the morphological features of dendrites and dendritic spines of pyramidal neurons in hippocampus of AD model treated with canagliflozin. The model of AD was obtained by intracerebroventricular injection of streptozotocin. Then, the rats were divided into 3 groups: vehicle, donepezil, and canagliflozin. The injections were i.c.v. administered for 7 days. Behavioral tests were performed to evaluate memory, anxiety, and motor functions. Brain tissues were processed by Golgi impregnation method. Pyramidal neurons in the CA1 region were examined using Neurolucida software. Dendritic branching, total dendrite length, dendritic spine density, and dendritic spine types were analyzed. Compared to the vehicle group, the donepezil group and the canagliflozin group exhibited significantly higher dendritic branches (p = 0.0273, p = 0.0195) and total dendrite length (p = 0.0171, p = 0.0360), respectively. The total dendritic spine density (p < 0.0001) and the mushroom-type dendritic spine density (p = 0.0001) were significantly low in the donepezil group compared to the vehicle group. However, canagliflozin did not induce any significant alterations in the dendritic spine density. Canagliflozin treatment was as effective as donepezil treatment on hippocampal dendrite morphology. This morphological framework, indicating dendritic plasticity and remodeling, serve to better understand the cellular effects of canagliflozin. Therefore, our study may contribute to the development of novel strategies for therapy of AD.},
}

Animals
*Canagliflozin/pharmacology/administration & dosage
*Alzheimer Disease/pathology/chemically induced/drug therapy
Male
Streptozocin/administration & dosage
*Dendrites/drug effects/pathology
Rats
*Hippocampus/drug effects/pathology
Disease Models, Animal
Donepezil/pharmacology
Dendritic Spines/drug effects/pathology
Pyramidal Cells/drug effects/pathology
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
Rats, Wistar
Rats, Sprague-Dawley